Glucokinase Activators

ABSTRACT

Compounds are provided for use with glucokinase that comprise the formula: 
     
       
         
         
             
             
         
       
     
     wherein the variables are as defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/054,052, filed May 16, 2008, and of U.S. Provisional Application No.61/108,370, filed on Oct. 24, 2008, which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to compounds that may be used to activatehexokinases, as well as compositions of matter, kits and articles ofmanufacture comprising these compounds. The invention also relates tomethods for activating hexokinases and treatment methods using compoundsaccording to the present invention. In addition, the invention relatesto methods of making the compounds of the present invention, as well asintermediates useful in such methods. In particular, the presentinvention relates to glucokinase activators, compositions of matter,kits and articles of manufacture comprising these compounds, methods foractivating glucokinase, and methods of making the activators.

BACKGROUND OF THE INVENTION

Glucokinase (GK, Hexokinase IV) is one of four hexokinases that arefound in mammals (Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer,ed.) Academic Press, New York, N.Y., pages 1-48, 1973). The hexokinasescatalyze the first step in the metabolism of glucose, i.e., theconversion of glucose to glucose-6-phosphate. Glucokinase is foundprincipally in pancreatic β-cells and liver parenchymal cells, two celltypes that are known to play critical roles in whole-body glucosehomeostasis. Specifically, GK is a rate-controlling enzyme for glucosemetabolism in these two cell types (Chipkin, S. R., Kelly, K. L., andRuderman, N. B. in Joslin's Diabetes (C. R. Khan and G. C. Wier, eds.),Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994).

The concentration of glucose at which GK demonstrates half-maximalactivity is approximately 8 mM. The other three hexokinases aresaturated with glucose at much lower concentrations (<1 mM). Therefore,the flux of glucose through the GK pathway rises as the concentration ofglucose in the blood increases from fasting levels (5 mM) topostprandial levels following a carbohydrate-containing meal (about10-15 mM) (Printz, R. G., Magnuson, M. A., and Granner, D. K. in Ann.Rev. Nutrition Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick,eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993).These findings suggest that GK functions as a glucose sensor in β-cellsand hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer. JPhysiol. 246, E1-E13, 1984).

More recently, studies in transgenic animals confirmed that GK doesindeed play a critical role in whole-body glucose homeostasis. Animalsthat do not express GK die within days of birth with severe diabetes,while animals overexpressing GK have improved glucose tolerance (Grupe,A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T.,Riu, E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increasein glucose exposure is coupled through GK in β-cells to increasedinsulin secretion and in hepatocytes to increased glycogen depositionand perhaps decreased glucose production.

The finding that type II maturity-onset diabetes of the young (MODY-2)is caused by loss of function mutations in the GK gene suggests that GKalso functions as a glucose sensor in humans (Liang, Y., Kesavan, P.,Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidencesupporting an important role for GK in the regulation of glucosemetabolism in humans was provided by the identification of patients thatexpress a mutant form of GK with increased enzymatic activity. Thesepatients exhibit a fasting hypoglycemia associated with aninappropriately elevated level of plasma insulin (Glaser, B., Kesavan,P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998).Accordingly, compounds that activate GK and, thereby, increase thesensitivity of the GK sensor system are expected to be useful in thetreatment of the hyperglycemia characteristic of all type II diabetes.Glucokinase activators should increase the flux of glucose metabolism inβ-cells and hepatocytes, which will be coupled to increased insulinsecretion.

There is a continued need to find new therapeutic agents to treat humandiseases. The hexokinases, specifically but not limited to glucokinase,are especially attractive targets for the discovery of new therapeuticsdue to their important role in diabetes, hyperglycemia and otherdiseases.

SUMMARY OF THE INVENTION

The present invention relates to compounds that activate glucokinase.The present invention also provides compositions, articles ofmanufacture and kits comprising these compounds. In addition, theinvention relates to methods of making the compounds of the presentinvention, as well as intermediates useful in such methods.

In one embodiment, a pharmaceutical composition is provided thatcomprises a glucokinase activator according to the present invention asan active ingredient. Pharmaceutical compositions according to theinvention may optionally comprise 0.001%-100% of one or more activatorsof this invention. These pharmaceutical compositions may be administeredor coadministered by a wide variety of routes, including for example,orally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, or intrathecally. The compositionsmay also be administered or coadministered in slow release dosage forms.

The invention is also directed to kits and other articles of manufacturefor treating disease states associated with glucokinase.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one glucokinase activator of the present inventionin combination with instructions. The instructions may indicate thedisease state for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one glucokinase activator ofthe present invention in combination with packaging materials. Thepackaging material may comprise a container for housing the composition.The container may optionally comprise a label indicating the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also optionally compriseadditional components, such as syringes for administration of thecomposition. The kit may comprise the composition in single or multipledose forms.

Also provided are methods for preparing compounds, compositions and kitsaccording to the present invention. For example, several syntheticschemes are provided herein for synthesizing compounds according to thepresent invention.

Also provided are methods for using compounds, compositions, kits andarticles of manufacture according to the present invention.

In one embodiment, the compounds, compositions, kits and articles ofmanufacture are used to modulate glucokinase. In particular, thecompounds, compositions, kits and articles of manufacture can be used toactivate glucokinase.

In another embodiment, the compounds, compositions, kits and articles ofmanufacture are used to treat a disease state for which increasingglucokinase activity ameliorates the pathology and/or symptomology ofthe disease state.

In another embodiment, a compound is administered to a subject whereinglucokinase activity within the subject is altered and, in oneembodiment, increased.

In another embodiment, a prodrug of a compound is administered to asubject that is converted to the compound in vivo where it activatesglucokinase.

In another embodiment, a method of activating glucokinase is providedthat comprises contacting glucokinase with a compound according to thepresent invention.

In another embodiment, a method of activating glucokinase is providedthat comprises causing a compound according to the present invention tobe present in a subject in order to activate glucokinase in vivo.

In another embodiment, a method of activating glucokinase is providedthat comprises administering a first compound to a subject that isconverted in vivo to a second compound wherein the second compoundactivates glucokinase in vivo. It is noted that the compounds of thepresent invention may be the first or second compounds.

In another embodiment, a therapeutic method is provided that comprisesadministering a compound according to the present invention.

In another embodiment, a method of treating a condition in a patientthat is known to be mediated by glucokinase, or which is known to betreated by glucokinase activators, is provided comprising administeringto the patient a therapeutically effective amount of a compoundaccording to the present invention.

In another embodiment, a method is provided for treating a disease statefor which increasing glucokinase activity ameliorates the pathologyand/or symptomology of the disease state, the method comprising: causinga compound according to the present invention to be present in a subjectin a therapeutically effective amount for the disease state.

In another embodiment, a method is provided for treating a disease statefor which increasing glucokinase activity ameliorates the pathologyand/or symptomology of the disease state, the method comprising:administering a first compound to a subject that is converted in vivo toa second compound such that the second compound is present in thesubject in a therapeutically effective amount for the disease state. Itis noted that the compounds of the present invention may be the first orsecond compounds.

In another embodiment, a method is provided for treating a disease statefor which increasing glucokinase activity ameliorates the pathologyand/or symptomology of the disease state, the method comprising:administering a compound according to the present invention to a subjectsuch that the compound is present in the subject in a therapeuticallyeffective amount for the disease state.

In another embodiment, a method is provided for using a compoundaccording to the present invention in order to manufacture a medicamentfor use in the treatment of a disease state that is known to be mediatedby glucokinase, or that is known to be treated by glucokinaseactivators.

It is noted in regard to all of the above embodiments that the presentinvention is intended to encompass all pharmaceutically acceptableionized forms (e.g., salts) and solvates (e.g., hydrates) of thecompounds, regardless of whether such ionized forms and solvates arespecified since it is well know in the art to administer pharmaceuticalagents in an ionized or solvated form. It is also noted that unless aparticular stereochemistry is specified, recitation of a compound isintended to encompass all possible stereoisomers (e.g., enantiomers ordiastereomers depending on the number of chiral centers), independent ofwhether the compound is present as an individual isomer or a mixture ofisomers. Further, unless otherwise specified, recitation of a compoundis intended to encompass all possible resonance forms and tautomers.With regard to the claims, the language “compound comprising theformula” is intended to encompass the compound and all pharmaceuticallyacceptable ionized forms and solvates, all possible stereoisomers, andall possible resonance forms and tautomers unless otherwise specificallyspecified in the particular claim.

It is further noted that prodrugs may also be administered which arealtered in vivo and become a compound according to the presentinvention. The various methods of using the compounds of the presentinvention are intended, regardless of whether prodrug delivery isspecified, to encompass the administration of a prodrug that isconverted in vivo to a compound according to the present invention. Itis also noted that certain compounds of the present invention may bealtered in vivo prior to activating glucokinase and thus may themselvesbe prodrugs for another compound. Such prodrugs of another compound mayor may not themselves independently have glucokinase activity.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates SEQ. ID No. 1 referred to in this application.

DEFINITIONS

Unless otherwise stated, the following terms used in the specificationand claims shall have the following meanings for the purposes of thisApplication.

It is noted that, as used in the specification and the appended claims,the singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise. Further, definitions of standardchemistry terms may be found in reference works, including Carey andSundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.” Vols. A (2000) and B(2001), Plenum Press, New York. Also, unless otherwise indicated,conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology, within theskill of the art are employed.

“Alicyclic” means a moiety comprising a non-aromatic ring structure.Alicyclic moieties may be saturated or partially unsaturated with one,two or more double or triple bonds. Alicyclic moieties may alsooptionally comprise heteroatoms such as nitrogen, oxygen and sulfur. Thenitrogen atoms can be optionally quaternerized or oxidized and thesulfur atoms can be optionally oxidized. Examples of alicyclic moietiesinclude, but are not limited to moieties with (C₃₋₈) rings such ascyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene,cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.

“Aliphatic” means a moiety characterized by a straight or branched chainarrangement of constituent carbon atoms and may be saturated orpartially unsaturated with one, two or more double or triple bonds.

“Alkenyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon double bond (—CR═CR′— or —CR═CR′R″, wherein R,R′ and R″ are each independently hydrogen or further substituents).Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl,hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and thelike. In particular embodiments, “alkenyl,” either alone or representedalong with another radical, can be a (C₂₋₂₀)alkenyl, a (C₂₋₁₅)alkenyl, a(C₂₋₁₀)alkenyl, a (C₂₋₅)alkenyl or a (C₂₋₃)alkenyl. Alternatively,“alkenyl,” either alone or represented along with another radical, canbe a (C₂)alkenyl, a (C₃)alkenyl or a (C₄)alkenyl.

“Alkenylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon double bonds (—CR═CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkenylene include ethene-1,2-diyl, propene-1,3-diyl,methylene-1,1-diyl, and the like. In particular embodiments,“alkenylene,” either alone or represented along with another radical,can be a (C₂₋₂₀) alkenylene, a (C₂₋₁₅) alkenylene, a (C₂₋₁₀) alkenylene,a (C₂₋₅) alkenylene or a (C₂₋₃) alkenylene. Alternatively, “alkenylene,”either alone or represented along with another radical, can be a (C₂)alkenylene, a (C₃) alkenylene or a (C₄) alkenylene.

“Alkoxy” means an oxygen moiety having a further alkyl substituent. Thealkoxy groups of the present invention can be optionally substituted.

“Alkyl” represented by itself means a straight or branched, saturatedaliphatic radical having a chain of carbon atoms, optionally with one ormore of the carbon atoms being replaced with oxygen (See “oxaalkyl”), acarbonyl group (See “oxoalkyl”), sulfur (See “thioalkyl”), and/ornitrogen (See “azaalkyl”). (C_(X))alkyl and (C_(X-Y))alkyl are typicallyused where X and Y indicate the number of carbon atoms in the chain. Forexample, (C₁₋₆)alkyl includes alkyls that have a chain of between 1 and6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl,2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl,and the like). Alkyl represented along with another radical (e.g., as inarylalkyl, heteroarylalkyl and the like) means a straight or branched,saturated or unsaturated aliphatic divalent radical having the number ofatoms indicated or when no atoms are indicated means a bond (e.g.,(C₆₋₁₀)aryl(C₁₋₃)alkyl includes, benzyl, phenethyl, 1-phenylethyl,3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl and the like). Inparticular embodiments, “alkyl,” either alone or represented along withanother radical, can be a (C₁₋₂₀)alkyl, a (C₁₋₁₅)alkyl, a (C₁₋₁₀)alkyl,a (C₁₋₅)alkyl or a (C₁₋₃)alkyl. Alternatively, “alkyl,” either alone orrepresented along with another radical, can be a (C₁)alkyl, a (C₂)alkylor a (C₃)alkyl.

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated or unsaturated, aliphatic, divalent radical. (C_(X))alkyleneand (C_(X-Y))alkylene are typically used where X and Y indicate thenumber of carbon atoms in the chain. For example, (C₁₋₆)alkyleneincludes methylene (—CH₂—), ethylene (—CH₂CH₂—), trimethylene(—CH₂CH₂CH₂—), tetramethylene (—CH₂CH₂CH₂CH₂—) 2-butenylene(—CH₂CH═CHCH₂—), 2-methyltetramethylene (—CH₂CH(CH₃)CH₂CH₂—),pentamethylene (—CH₂CH₂CH₂CH₂CH₂—) and the like. In particularembodiments, “alkylene,” either alone or represented along with anotherradical, can be a (C₁₋₂₀)alkylene, a (C₁₋₁₅)alkylene, a (C₁₋₁₀)alkylene,a (C₁₋₅)alkylene or a (C₁₋₃)alkylene. Alternatively, “alkylene,” eitheralone or represented along with another radical, can be a (C₁)alkylene,a (C₂)alkylene or a (C₃)alkylene.

“Alkylidene” means a straight or branched, saturated or unsaturated,aliphatic radical connected to the parent molecule by a double bond.(C_(X))alkylidene and (C_(X-Y))alkylidene are typically used where X andY indicate the number of carbon atoms in the chain. For example,(C₁₋₆)alkylidene includes methylene (═CH₂), ethylidene (═CHCH₃),isopropylidene (═C(CH₃)₂), propylidene (═CHCH₂CH₃), allylidene(═CH—CH═CH₂), and the like. In particular embodiments, “alkylidene,”either alone or represented along with another radical, can be a(C₁₋₂₀)alkylidene, a (C₁₋₁₅)alkylidene, a (C₁₋₁₀)alkylidene, a(C₁₋₅)alkylidene or a (C₁₋₃)alkylidene. Alternatively, “alkylidene,”either alone or represented along with another radical, can be a(C₁)alkylidene, a (C₂)alkylidene or a (C₃)alkylidene.

“Alkynyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon triple bond (—C≡C— or —C≡CR, wherein R ishydrogen or a further substituent). Examples of alkynyl include ethynyl,propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. In particularembodiments, “alkynyl,” either alone or represented along with anotherradical, can be a (C₂₋₂₀)alkynyl, a (C₂₋₁₅)alkynyl, a (C₂₋₁₀)alkynyl, a(C₂₋₅)alkynyl or a (C₂₋₃)alkynyl. Alternatively, “alkynyl,” either aloneor represented along with another radical, can be a (C₂)alkynyl, a(C₃)alkynyl or a (C₄)alkynyl.

“Alkynylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon triple bonds (—CR≡CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkynylene include ethyne-1,2-diyl, propyne-1,3-diyl, and the like. Inparticular embodiments, “alkynylene,” either alone or represented alongwith another radical, can be a (C₂₋₂₀) alkynylene, a (C₂₋₁₅) alkynylene,a (C₂₋₁₀) alkynylene, a (C₂₋₅) alkynylene or a (C₂₋₃) alkynylene.Alternatively, “alkenylene,” either alone or represented along withanother radical, can be a (C₂) alkynylene, a (C₃) alkynylene or a (C₄)alkynylene.

“Amido” means the radical —C(═O)—NR—, —C(═O)—NRR′, —NR—C(═O)— and/or—NR—C(═O)R′, wherein each R and R′ are independently hydrogen or afurther substituent.

“Amino” means a nitrogen moiety having two further substituents where,for example, a hydrogen or carbon atom is attached to the nitrogen. Forexample, representative amino groups include —NH₂, —NHCH₃, —N(CH₃)₂,—NH((C₁₋₁₀)alkyl), —N((C₁₋₁₀)alkyl)₂, —NH(aryl), —NH(heteroaryl),—N(aryl)₂, —N(heteroaryl)₂, and the like. Optionally, the twosubstituents together with the nitrogen may also form a ring. Unlessindicated otherwise, the compounds of the invention containing aminomoieties may include protected derivatives thereof. Suitable protectinggroups for amino moieties include acetyl, tert-butoxycarbonyl,benzyloxycarbonyl, and the like.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp² hybridizedand the total number of pi electrons is equal to 4n+2. An aromatic ringmay be such that the ring atoms are only carbon atoms or may includecarbon and non-carbon atoms (See “heteroaryl”).

“Aryl” means a monocyclic or polycyclic ring assembly wherein each ringis aromatic or when fused with one or more rings forms an aromatic ringassembly. If one or more ring atoms is not carbon (e.g., N, S), the arylis a heteroaryl. (C_(X))aryl and (C_(X-Y))aryl are typically used whereX and Y indicate the number of carbon atoms in the ring. In particularembodiments, “aryl,” either alone or represented along with anotherradical, can be a (C₃₋₁₄)aryl, a (C₃₋₁₀)aryl, a (C₃₋₇)aryl, a(C₈₋₁₀)aryl or a (C₅₋₇)aryl. Alternatively, “aryl,” either alone orrepresented along with another radical, can be a (C₅)aryl, a (C₆)aryl, a(C₇)aryl, a (C₈)aryl, a (C₉)aryl or a (C₁₀)aryl.

“Azaalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with substitutedor unsubstituted nitrogen atoms (—NR— or —NRR′, wherein R and R′ areeach independently hydrogen or further substituents). For example, a(C₁₋₁₀)azaalkyl refers to a chain comprising between 1 and 10 carbonsand one or more nitrogen atoms.

“Bicycloalkyl” means a saturated or partially unsaturated fused, spiroor bridged bicyclic ring assembly. In particular embodiments,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₄₋₁₅)bicycloalkyl, a (C₄₋₁₀)bicycloalkyl, a(C₆₋₁₀)bicycloalkyl or a (C₈₋₁₀)bicycloalkyl. Alternatively,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₈)bicycloalkyl, a (C₉)bicycloalkyl or a (C₁₀)bicycloalkyl.

“Bicycloaryl” means a fused, spiro or bridged bicyclic ring assemblywherein at least one of the rings comprising the assembly is aromatic.(C_(X))bicycloaryl and (C_(X-Y))bicycloaryl are typically used where Xand Y indicate the number of carbon atoms in the bicyclic ring assemblyand directly attached to the ring. In particular embodiments,“bicycloaryl,” either alone or represented along with another radical,can be a (a (C₄₋₁₅)bicycloaryl, a (C₄₋₁₀)bicycloaryl, a(C₆₋₁₀)bicycloaryl or a (C₈₋₁₀)bicycloaryl. Alternatively,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₈)bicycloaryl, a (C₉)bicycloaryl or a (C₁₀)bicycloaryl.

“Bridging ring” and “bridged ring” as used herein refer to a ring thatis bonded to another ring to form a compound having a bicyclic orpolycyclic structure where two ring atoms that are common to both ringsare not directly bound to each other. Non-exclusive examples of commoncompounds having a bridging ring include borneol, norbornane,7-oxabicyclo[2.2.1]heptane, and the like. One or both rings of thebicyclic system may also comprise heteroatoms.

“Carbamoyl” means the radical —OC(O)NRR′, wherein R and R′ are eachindependently hydrogen or further substituents.

“Carbocycle” means a ring consisting of carbon atoms.

“Carbonyl” means the radical —C(═O)— and/or —C(═O)R, wherein R ishydrogen or a further substituent. It is noted that the carbonyl radicalmay be further substituted with a variety of substituents to formdifferent carbonyl groups including acids, acid halides, aldehydes,amides, esters, and ketones.

“Carboxy” means the radical —C(═O)—O— and/or —C(═O)—OR, wherein R ishydrogen or a further substituent. It is noted that compounds of theinvention containing carboxy moieties may include protected derivativesthereof, i.e., where the oxygen is substituted with a protecting group.Suitable protecting groups for carboxy moieties include benzyl,tert-butyl, and the like.

“Cyano” means the radical —CN.

“Cycloalkyl” means a non-aromatic, saturated or partially unsaturated,monocyclic, bicyclic or polycyclic ring assembly. (C_(X))cycloalkyl and(C_(X-Y))cycloalkyl are typically used where X and Y indicate the numberof carbon atoms in the ring assembly. For example, (C₃₋₁₀)cycloalkylincludes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl,decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,2-oxobicyclo[2.2.1]hept-1-yl, and the like. In particular embodiments,“cycloalkyl,” either alone or represented along with another radical,can be a (C₃₋₁₄)cycloalkyl, a (C₃₋₁₀)cycloalkyl, a (C₃₋₇)cycloalkyl, a(C₈₋₁₀)cycloalkyl or a (C₅₋₇)cycloalkyl. Alternatively, “cycloalkyl,”either alone or represented along with another radical, can be a(C₅)cycloalkyl, a (C₆)cycloalkyl, a (C₇)cycloalkyl, a (C₈)cycloalkyl, a(C₉)cycloalkyl or a (C₁₀)cycloalkyl.

“Cycloalkylene” means a divalent, saturated or partially unsaturated,monocyclic, bicyclic or polycyclic ring assembly. (C_(X))cycloalkyleneand (C_(X-Y))cycloalkylene are typically used where X and Y indicate thenumber of carbon atoms in the ring assembly. In particular embodiments,“cycloalkylene,” either alone or represented along with another radical,can be a (C₃₋₁₄)cycloalkylene, a (C₃₋₁₀)cycloalkylene, a(C₃₋₇)cycloalkylene, a (C₈₋₁₀)cycloalkylene or a (C₅₋₇)cycloalkylene.Alternatively, “cycloalkylene,” either alone or represented along withanother radical, can be a (C₅)cycloalkylene, a (C₆)cycloalkylene, a(C₇)cycloalkylene, a (C₈)cycloalkylene, a (C₉)cycloalkylene or a(C₁₀)cycloalkylene.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Fused ring” as used herein refers to a ring that is bonded to anotherring to form a compound having a bicyclic structure where the ring atomsthat are common to both rings are directly bound to each other.Non-exclusive examples of common fused rings include decalin,naphthalene, anthracene, phenanthrene, indole, furan, benzofuran,quinoline, and the like.

Compounds having fused ring systems may be saturated, partiallysaturated, carbocyclics, heterocyclics, aromatics, heteroaromatics, andthe like.

“Halo” means fluoro, chloro, bromo or iodo.

“Heteroalkyl” means alkyl, as defined in this Application, provided thatone or more of the atoms within the alkyl chain is a heteroatom. Inparticular embodiments, “heteroalkyl,” either alone or represented alongwith another radical, can be a hetero(C₁₋₂₀)alkyl, a hetero(C₁₋₁₅)alkyl,a hetero(C₁₋₁₀)alkyl, a hetero(C₁₋₅)alkyl, a hetero(C₁₋₃)alkyl or ahetero(C₁₋₂)alkyl. Alternatively, “heteroalkyl,” either alone orrepresented along with another radical, can be a hetero(C₁)alkyl, ahetero(C₂)alkyl or a hetero(C₃)alkyl.

“Heteroaryl” means a monocyclic, bicyclic or polycyclic aromatic groupwherein at least one ring atom is a heteroatom and the remaining ringatoms are carbon. Monocyclic heteroaryl groups include, but are notlimited to, cyclic aromatic groups having five or six ring atoms,wherein at least one ring atom is a heteroatom and the remaining ringatoms are carbon. The nitrogen atoms can be optionally quaternerized andthe sulfur atoms can be optionally oxidized. Heteroaryl groups of thisinvention include, but are not limited to, those derived from furan,imidazole, isothiazole, isoxazole, oxadiazole, oxazole,1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrroline, thiazole, 1,3,4-thiadiazole, triazole and tetrazole.“Heteroaryl” also includes, but is not limited to, bicyclic or tricyclicrings, wherein the heteroaryl ring is fused to one or two ringsindependently selected from the group consisting of an aryl ring, acycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroarylor heterocycloalkyl ring. These bicyclic or tricyclic heteroarylsinclude, but are not limited to, those derived from benzo[b]furan,benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline,thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine,indolizine, imidazo[1,2a]pyridine, quinoline, isoquinoline, phthalazine,quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole,indoline, benzoxazole, benzopyrazole, benzothiazole,imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine,pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine,carbazole, acridine, phenazine, phenothiazene, phenoxazine,1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole and2(1H)-pyridinone. The bicyclic or tricyclic heteroaryl rings can beattached to the parent molecule through either the heteroaryl groupitself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl groupto which it is fused. The heteroaryl groups of this invention can besubstituted or unsubstituted. In particular embodiments, “heteroaryl,”either alone or represented along with another radical, can be ahetero(C₁₋₁₃)aryl, a hetero(C₂₋₁₃)aryl, a hetero(C₂₋₆)aryl, ahetero(C₃₋₉)aryl or a hetero(C₅₋₉)aryl. Alternatively, “heteroaryl,”either alone or represented along with another radical, can be ahetero(C₃)aryl, a hetero(C₄)aryl, a hetero(C₅)aryl, a hetero(C₆)aryl, ahetero(C₇)aryl, a hetero(C₈)aryl or a hetero(C₉)aryl.

“Heteroatom” refers to an atom that is not a carbon atom. Particularexamples of heteroatoms include, but are not limited to, nitrogen,oxygen, and sulfur.

“Heteroatom moiety” includes a moiety where the atom by which the moietyis attached is not a carbon. Examples of heteroatom moieties include—NR—, —N⁺(O⁻)═, —O—, —S— or —S(O)₂—, wherein R is hydrogen or a furthersubstituent.

“Heterobicycloalkyl” means bicycloalkyl, as defined in this Application,provided that one or more of the atoms within the ring is a heteroatom.For example hetero(C₉₋₁₂)bicycloalkyl as used in this applicationincludes, but is not limited to, 3-aza-bicyclo[4.1.0]hept-3-yl,2-aza-bicyclo[3.1.0]hex-2-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, and thelike. In particular embodiments, “heterobicycloalkyl,” either alone orrepresented along with another radical, can be ahetero(C₁₋₁₄)bicycloalkyl, a hetero(C₄₋₁₄)bicycloalkyl, ahetero(C₄₋₉)bicycloalkyl or a hetero(C₅₋₉)bicycloalkyl. Alternatively,“heterobicycloalkyl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloalkyl, hetero(C₆)bicycloalkyl,hetero(C₇)bicycloalkyl, hetero(C₈)bicycloalkyl or ahetero(C₉)bicycloalkyl.

“Heterobicycloaryl” means bicycloaryl, as defined in this Application,provided that one or more of the atoms within the ring is a heteroatom.For example, hetero(C₄₋₁₂)bicycloaryl as used in this Applicationincludes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl,tetrahydroisoquinolinyl, and the like. In particular embodiments,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₄)bicycloaryl, a hetero(C₄₋₁₄)bicycloaryl,a hetero(C₄₋₉)bicycloaryl or a hetero(C₅₋₉)bicycloaryl. Alternatively,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloaryl, hetero(C₆)bicycloaryl,hetero(C₇)bicycloaryl, hetero(C₈)bicycloaryl or a hetero(C₉)bicycloaryl.

“Heterocycloalkyl” means cycloalkyl, as defined in this Application,provided that one or more of the atoms forming the ring is a heteroatomselected, independently from N, O, or S. Non-exclusive examples ofheterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl,pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl,1,3-dioxanyl, 1,4-dioxanyl and the like. In particular embodiments,“heterocycloalkyl,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₃)cycloalkyl, a hetero(C₁₋₉)cycloalkyl, ahetero(C₁₋₆)cycloalkyl, a hetero(C₅₋₉)cycloalkyl or ahetero(C₂₋₆)cycloalkyl. Alternatively, “heterocycloalkyl,” either aloneor represented along with another radical, can be ahetero(C₂)cycloalkyl, a hetero(C₃)cycloalkyl, a hetero(C₄)cycloalkyl, ahetero(C₅)cycloalkyl, a hetero(C₆)cycloalkyl, hetero(C₇)cycloalkyl,hetero(C₈)cycloalkyl or a hetero(C₉)cycloalkyl.

“Heterocycloalkylene” means cycloalkylene, as defined in thisApplication, provided that one or more of the ring member carbon atomsis replaced by a heteroatom. In particular embodiments,“heterocycloalkylene,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₃)cycloalkylene, ahetero(C₁₋₉)cycloalkylene, a hetero(C₁₋₆)cycloalkylene, ahetero(C₅₋₉)cycloalkylene or a hetero(C₂₋₆)cycloalkylene. Alternatively,“heterocycloalkylene,” either alone or represented along with anotherradical, can be a hetero(C₂)cycloalkylene, a hetero(C₃)cycloalkylene, ahetero(C₄)cycloalkylene, a hetero(C₅)cycloalkylene, ahetero(C₆)cycloalkylene, hetero(C₇)cycloalkylene,hetero(C₈)cycloalkylene or a hetero(C₉)cycloalkylene.

“Hydroxy” means the radical —OH.

“IC₅₀” means the molar concentration of an inhibitor that produces 50%inhibition of the target enzyme.

“Imino” means the radical —CR(═NR′) and/or —C(═NR′)—, wherein R and R′are each independently hydrogen or a further substituent.

“Isomers” means compounds having identical molecular formulae butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers.”Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers.” A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter.” A compound with one chiral center has two enantiomeric forms ofopposite chirality. A mixture of the two enantiomeric forms is termed a“racemic mixture.” A compound that has more than one chiral center has2^(n-1) enantiomeric pairs, where n is the number of chiral centers.

Compounds with more than one chiral center may exist as ether anindividual diastereomer or as a mixture of diastereomers, termed a“diastereomeric mixture.” When one chiral center is present astereoisomer may be characterized by the absolute configuration of thatchiral center. Absolute configuration refers to the arrangement in spaceof the substituents attached to the chiral center. Enantiomers arecharacterized by the absolute configuration of their chiral centers anddescribed by the R- and S-sequencing rules of Cahn, Ingold and Prelog.Conventions for stereochemical nomenclature, methods for thedetermination of stereochemistry and the separation of stereoisomers arewell known in the art (e.g., see “Advanced Organic Chemistry”, 4thedition, March, Jerry, John Wiley & Sons, New York, 1992).

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under reaction (e.g., alkylating) conditions.Examples of leaving groups include, but are not limited to, halo (e.g.,F, Cl, Br and I), alkyl (e.g., methyl and ethyl) and sulfonyloxy (e.g.,mesyloxy, ethanesulfonyloxy, benzenesulfonyloxy and tosyloxy),thiomethyl, thienyloxy, dihalophosphinoyloxy, tetrahalophosphoxy,benzyloxy, isopropyloxy, acyloxy, and the like.

“Moiety providing X atom separation” and “linker providing X atomseparation” between two other moieties mean that the chain of atomsdirectly linking the two other moieties is X atoms in length. When X isgiven as a range (e.g., X₁-X₂), then the chain of atoms is at least X₁and not more than X₂ atoms in length. It is understood that the chain ofatoms can be formed from a combination of atoms including, for example,carbon, nitrogen, sulfur and oxygen atoms. Further, each atom canoptionally be bound to one or more substituents, as valencies allow. Inaddition, the chain of atoms can form part of a ring. Accordingly, inone embodiment, a moiety providing X atom separation between two othermoieties (R and R′) can be represented by R-(L)_(X)-R′ where each L isindependently selected from the group consisting of CR″R″′, NR″″, O, S,CO, CS, C═NR″″, SO, SO₂, and the like, where any two or more of R″, R″′,R″″ and R″″′ can be taken together to form a substituted orunsubstituted ring.

“Nitro” means the radical —NO₂.

“Oxaalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with oxygen atoms(—O— or —OR, wherein R is hydrogen or a further substituent). Forexample, an oxa(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more oxygen atoms.

“Oxoalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with carbonylgroups (—C(═O)— or —C(═O)—R, wherein R is hydrogen or a furthersubstituent). The carbonyl group may be an aldehyde, ketone, ester,amide, acid, or acid halide. For example, an oxo(C₁₋₁₀)alkyl refers to achain comprising between 1 and 10 carbon atoms and one or more carbonylgroups.

“Oxy” means the radical —O— or —OR, wherein R is hydrogen or a furthersubstituent. Accordingly, it is noted that the oxy radical may befurther substituted with a variety of substituents to form different oxygroups including hydroxy, alkoxy, aryloxy, heteroaryloxy or carbonyloxy.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of thepresent invention which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as aceticacid, propionic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonicacid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

“Polycyclic ring” includes bicyclic and multi-cyclic rings. Theindividual rings comprising the polycyclic ring can be fused, spiro orbridging rings.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an inhibitor according to the present invention. The prodrug itselfmay or may not also have activity with respect to a given targetprotein. For example, a compound comprising a hydroxy group may beadministered as an ester that is converted by hydrolysis in vivo to thehydroxy compound. Suitable esters that may be converted in vivo intohydroxy compounds include acetates, citrates, lactates, phosphates,tartrates, malonates, oxalates, salicylates, propionates, succinates,fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates,isethionates, di-p-toluoyltartrates, methanesulfonates,ethanesulfonates, benzenesulfonates, p-toluenesulfonates,cyclohexylsulfamates, quinates, esters of amino acids, and the like.Similarly, a compound comprising an amine group may be administered asan amide that is converted by hydrolysis in vivo to the amine compound.

“Protected derivatives” means derivatives of inhibitors in which areactive site or sites are blocked with protecting groups. Protectedderivatives are useful in the preparation of inhibitors or in themselvesmay be active as inhibitors. A comprehensive list of suitable protectinggroups can be found in T.W. Greene, Protecting Groups in OrganicSynthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

“Ring” and “ring assembly” means a carbocyclic or a heterocyclic systemand includes aromatic and non-aromatic systems. The system can bemonocyclic, bicyclic or polycyclic. In addition, for bicyclic andpolycyclic systems, the individual rings comprising the polycyclic ringcan be fused, spiro or bridging rings.

“Subject” and “patient” include humans, non-human mammals (e.g., dogs,cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like)and non-mammals (e.g., birds, and the like).

“Substituent convertible to hydrogen in vivo” means any group that isconvertible to a hydrogen atom by enzymological or chemical meansincluding, but not limited to, hydrolysis and hydrogenolysis. Examplesinclude hydrolyzable groups, such as acyl groups, groups having anoxycarbonyl group, amino acid residues, peptide residues,o-nitrophenylsulfenyl, trimethylsilyl, tetrahydro-pyranyl,diphenylphosphinyl, and the like. Examples of acyl groups includeformyl, acetyl, trifluoroacetyl, and the like. Examples of groups havingan oxycarbonyl group include ethoxycarbonyl, t-butoxycarbonyl[(CH₃)₃C—OCO—], benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,vinyloxycarbonyl, β-(p-toluenesulfonyl)ethoxycarbonyl, and the like.Examples of suitable amino acid residues include amino acid residues perse and amino acid residues that are protected with a protecting group.Suitable amino acid residues include, but are not limited to, residuesof Gly (glycine), Ala (alanine; CH₃CH(NH₂)CO—), Arg (arginine), Asn(asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid),His (histidine), Ile (isoleucine), Leu (leucine; (CH₃)₂CHCH₂CH(NH₂)CO—),Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser(serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val(valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline),5-Hyl (5-hydroxylysine), Orn (ornithine) and β-Ala. Examples of suitableprotecting groups include those typically employed in peptide synthesis,including acyl groups (such as formyl and acetyl), arylmethyloxycarbonylgroups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl),t-butoxycarbonyl groups [(CH₃)₃C—OCO—], and the like. Suitable peptideresidues include peptide residues comprising two to five, and optionallytwo to three, of the aforesaid amino acid residues. Examples of suchpeptide residues include, but are not limited to, residues of suchpeptides as Ala-Ala [CH₃CH(NH₂)CO—NHCH(CH₃)CO—], Gly-Phe, Nva-Nva,Ala-Phe, Gly-Gly, Gly-Gly-Gly, Ala-Met, Met-Met, Leu-Met and Ala-Leu.The residues of these amino acids or peptides can be present instereochemical configurations of the D-form, the L-form or mixturesthereof. In addition, the amino acid or peptide residue may have anasymmetric carbon atom. Examples of suitable amino acid residues havingan asymmetric carbon atom include residues of Ala, Leu, Phe, Trp, Nva,Val, Met, Ser, Lys, Thr and Tyr. Peptide residues having an asymmetriccarbon atom include peptide residues having one or more constituentamino acid residues having an asymmetric carbon atom. Examples ofsuitable amino acid protecting groups include those typically employedin peptide synthesis, including acyl groups (such as formyl and acetyl),arylmethyloxycarbonyl groups (such as benzyloxycarbonyl andp-nitrobenzyloxycarbonyl), t-butoxycarbonyl groups [(CH₃)₃C—OCO—], andthe like. Other examples of substituents “convertible to hydrogen invivo” include reductively eliminable hydrogenolyzable groups. Examplesof suitable reductively eliminable hydrogenolyzable groups include, butare not limited to, arylsulfonyl groups (such as o-toluenesulfonyl);methyl groups substituted with phenyl or benzyloxy (such as benzyl,trityl and benzyloxymethyl); arylmethoxycarbonyl groups (such asbenzyloxycarbonyl and o-methoxy-benzyloxycarbonyl); andhalogenoethoxycarbonyl groups (such as β,β,β-trichloroethoxycarbonyl andβ-iodoethoxycarbonyl).

“Substituted or unsubstituted” means that a given moiety may consist ofonly hydrogen substituents through available valencies (unsubstituted)or may further comprise one or more non-hydrogen substituents throughavailable valencies (substituted) that are not otherwise specified bythe name of the given moiety. For example, isopropyl is an example of anethylene moiety that is substituted by —CH₃. In general, a non-hydrogensubstituent may be any substituent that may be bound to an atom of thegiven moiety that is specified to be substituted. Examples ofsubstituents include, but are not limited to, aldehyde, alicyclic,aliphatic, (C₁₋₁₀)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl,aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl,carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo,heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl,heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl,and oxoalkyl moieties, each of which may optionally also be substitutedor unsubstituted. In one particular embodiment, examples of substituentsinclude, but are not limited to, hydrogen, halo, nitro, cyano, thio,oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,(C₁₋₁₀)azaalkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl. In addition, the substituent is itselfoptionally substituted by a further substituent. In one particularembodiment, examples of the further substituent include, but are notlimited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl.

“Sulfinyl” means the radical —SO— and/or —SO—R, wherein R is hydrogen ora further substituent. It is noted that the sulfinyl radical may befurther substituted with a variety of substituents to form differentsulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters,and sulfoxides.

“Sulfonyl” means the radical —SO₂— and/or —SO₂—R, wherein R is hydrogenor a further substituent. It is noted that the sulfonyl radical may befurther substituted with a variety of substituents to form differentsulfonyl groups including sulfonic acids, sulfonamides, sulfonateesters, and sulfones.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Thio” denotes replacement of an oxygen by a sulfur and includes, but isnot limited to, —SR, —S— and ═S containing groups.

“Thioalkyl” means an alkyl, as defined above, except where one or moreof the carbon atoms forming the alkyl chain are replaced with sulfuratoms (—S— or —S—R, wherein R is hydrogen or a further substituent). Forexample, a thio(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more sulfur atoms.

“Thiocarbonyl” means the radical —C(═S)— and/or —C(═S)—R, wherein R ishydrogen or a further substituent. It is noted that the thiocarbonylradical may be further substituted with a variety of substituents toform different thiocarbonyl groups including thioacids, thioamides,thioesters, and thioketones.

“Treatment” or “treating” means any administration of a compound of thepresent invention and includes:

(1) preventing the disease from occurring in an animal which may bepredisposed to the disease but does not yet experience or display thepathology or symptomatology of the disease,

(2) inhibiting the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,arresting further development of the pathology and/or symptomatology),or

(3) ameliorating the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,reversing the pathology and/or symptomatology).

It is noted in regard to all of the definitions provided herein that thedefinitions should be interpreted as being open ended in the sense thatfurther substituents beyond those specified may be included. Hence, a C₁alkyl indicates that there is one carbon atom but does not indicate whatare the substituents on the carbon atom. Hence, a (C₁)alkyl comprisesmethyl (i.e., —CH₃) as well as —CRR′R″ where R, R′, and R″ may eachindependently be hydrogen or a further substituent where the atomattached to the carbon is a heteroatom or cyano. Hence, CF₃, CH₂OH andCH₂CN, for example, are all (C₁)alkyls. Similarly, terms such asalkylamino and the like comprise dialkylamino and the like.

A compound having a formula that is represented with a dashed bond isintended to include the formulae optionally having zero, one or moredouble bonds, as exemplified and shown below:

In addition, atoms making up the compounds of the present invention areintended to include all isotopic forms of such atoms. Isotopes, as usedherein, include those atoms having the same atomic number but differentmass numbers. By way of general example and without limitation, isotopesof hydrogen include tritium and deuterium, and isotopes of carboninclude ¹³C and ¹⁴C.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that may be used to modulatea hexokinase and, in particular, compounds that activate glucokinase(referred to herein as “GK”). The present invention also relates topharmaceutical compositions, kits and articles of manufacture comprisingsuch compounds. In addition, the present invention relates to methodsand intermediates useful for making the compounds. Further, the presentinvention relates to methods of using said compounds. It is noted thatthe compounds of the present invention may also possess activity forother hexokinase family members and thus may be used to address diseasestates associated with these other family members.

Glucokinase Activators

In one embodiment, glucokinase activators of the present invention havethe formula:

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein

-   -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₆ is -L₁-R₂₂;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   or any two R₅, R₆ and R₇ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In one variation of the above embodiment, R₁ is not5-(3-acetamidocyclobutyl)-1H-pyrazol-3-yl when R₅ and R₆, together withthe ring to which they are attached, form an unsubstituted indazol-1-yl.In another variation of the above embodiment, R₁ is not5-(2-chlorobenzyl)thiazol-2-yl when R₃ is phenyl and R₂, R₄, R₅, R₆ andR₇ are all hydrogen.

In another embodiment, glucokinase activators of the present inventionhave the formula:

-   -   wherein    -   m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8, 9, 10 and 11;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In still another embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In yet another embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In a further embodiment, glucokinase activators of the present inventionhave the formula:

-   -   wherein    -   q is selected from the group consisting of 3, 4 and 5;    -   each X is independently selected from the group consisting of        CR₁₄R₁₅, CO, CS, NR₁₆, O, S, SO and SO₂;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring, and    -   the remaining variables are as described above.

In one variation of the above embodiment, ring A is not5-(3-acetamidocyclobutyl)-1H-pyrazol-3-yl when R₅ and R₆, together withthe ring to which they are attached, form an unsubstituted indazol-1-yl.In another variation of the above embodiment, ring A is not5-(2-chlorobenzyl)thiazol-2-yl when R₃ is phenyl and R₂, R₄, R₅, R₆ andR₇ are all hydrogen.

In another embodiment, glucokinase activators of the present inventionhave the formula:

-   -   wherein    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   q is selected from the group consisting of 3, 4 and 5;    -   each X is independently selected from the group consisting of        CR₁₄R₁₅, CO, CS, NR₁₆, O, S, SO and SO₂;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring, and    -   the remaining variables are as described above.

In another embodiment, glucokinase activators of the present inventionhave the formula:

-   -   wherein    -   X₁, X₂ and X₃ are each independently selected from the group        consisting of CR₉R₁₀, CO, CS, C(NR₁₁), NR₁₂, S and O;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond,    -   or any two R₇, R₉, R₁₀, R₁₁ and R₁₂ are taken together to form a        substituted or unsubstituted ring.

In a further embodiment, glucokinase activators of the present inventionhave the formula:

-   -   wherein    -   X₁, X₂, X₃ and X₄ are each independently selected from the group        consisting of CR₉R₁₀, CO, CS, C(NR₁₁), NR₁₂, S and O;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond,    -   or any two R₇, R₉, R₁₀, R₁₁ and R₁₂ are taken together to form a        substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In still a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In one variation of the above embodiment, R₁ is not5-(3-acetamidocyclobutyl)-1H-pyrazol-3-yl when R₇ and each R₈ are allhydrogen.

In yet a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In one variation of the above embodiment, R₁ is not5-(3-acetamidocyclobutyl)-1H-pyrazol-3-yl when R₇ and each R₈ are allhydrogen.

In still another embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8, 9, 10 and 11;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In yet another embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   p′ is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6        and 7;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In a further embodiment, glucokinase activators of the present inventionhave the formula:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In still a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In yet a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   q is selected from the group consisting of 3, 4 and 5;    -   each X is independently selected from the group consisting of        CR₁₄R₁₅, CO, CS, NR₁₆, O, S, SO and SO₂;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In one variation of the above embodiment, ring A is not5-(3-acetamidocyclobutyl)-1H-pyrazol-3-yl when R₇ and each R₈ are allhydrogen.

In yet a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   q is selected from the group consisting of 3, 4 and 5;    -   each X is independently selected from the group consisting of        CR₁₄R₁₅, CO, CS, NR₁₆, O, S, SO and SO₂;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In another embodiment, glucokinase activators of the present inventionhave the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In still another embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n″ is selected from the group consisting of 0, 1 and 2;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In still another embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8, 9, 10 and 11;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In yet another embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   p′ is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6        and 7;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In a further embodiment, glucokinase activators of the present inventionhave the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In still a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In yet a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   q is selected from the group consisting of 3, 4 and 5;    -   each X is independently selected from the group consisting of        CR₁₄R₁₅, CO, CS, NR₁₆, O, S, SO and SO₂;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In yet a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   q is selected from the group consisting of 3, 4 and 5;    -   each X is independently selected from the group consisting of        CR₁₄R₁₅, CO, CS, NR₁₆, O, S, SO and SO₂;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In yet another embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In a further embodiment, glucokinase activators of the present inventionhave the formula:

-   -   wherein    -   n″ is selected from the group consisting of 0, 1 and 2;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In still another embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8, 9, 10 and 11;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In yet another embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   p′ is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6        and 7;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In a further embodiment, glucokinase activators of the present inventionhave the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In still a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In yet a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   q is selected from the group consisting of 3, 4 and 5;    -   each X is independently selected from the group consisting of        CR₁₄R₁₅, CO, CS, NR₁₆, O, S, SO and SO₂;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In yet a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n′ is selected from the group consisting of 0, 1, 2 and 3;    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   q is selected from the group consisting of 3, 4 and 5;    -   each X is independently selected from the group consisting of        CR₁₄R₁₅, CO, CS, NR₁₆, O, S, SO and SO₂;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In another embodiment, glucokinase activators of the present inventionhave the formula:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₅ or two R₈ are taken together to        form a substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In yet another embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8, 9, 10 and 11;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₅ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In a further embodiment, glucokinase activators of the present inventionhave the formula:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₅ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In still a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₅ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring; and    -   the remaining variables are as described above.

In yet a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   q is selected from the group consisting of 3, 4 and 5;    -   each X is independently selected from the group consisting of        CR₁₄R₁₅, CO, CS, NR₁₆, O, S, SO and SO₂;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₅ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In yet a further embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   q is selected from the group consisting of 3, 4 and 5;    -   each X is independently selected from the group consisting of        CR₁₄R₁₅, CO, CS, NR₁₆, O, S, SO and SO₂;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or R₈ and R₅ or two R₈ are taken together to        form a substituted or unsubstituted ring;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In still another embodiment, glucokinase activators of the presentinvention have the formula:

-   -   wherein    -   X₁, X₂ and X₃ are each independently selected from the group        consisting of CR₉R₁₀, CO, CS, C(NR₁₁), NR₁₂, S and O;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond,    -   or any two R₅, R₉, R₁₀, R₁₁ and R₁₂ are taken together to form a        substituted or unsubstituted ring; and    -   the remaining variables are as described above.

In another of its aspects, the present invention relates to methods ofmaking compounds that are useful as glucokinase activators. In oneembodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

to form a first reaction product having the formula

reacting the first reaction product with a compound having the formula

to form a second reaction product having the formula

treating the second reaction product to form a third reaction producthaving the formula

and

reacting the third reaction product with a compound having the formula

NHR₁R₂

to form a fourth reaction product having the formula

-   -   wherein    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₆ is -L₁-R₂₂;    -   or R₅ and R₆ are taken together to form a substituted or        unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈;    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring; and    -   G₁ and G₂ are each independently a leaving group.

In another embodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

to form a first reaction product having the formula

reacting the first reaction product with a compound having the formula

SHR₂₂

to form a second reaction product having the formula

treating the second reaction product to form a third reaction producthaving the formula

and

reacting the third reaction product with a compound having the formula

NHR₁R₂

to form a fourth reaction product having the formula

-   -   wherein    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   or R₅ and R₇ are taken together to form a substituted or        unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈;    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring; and    -   G₁ and G₂ are each independently a leaving group.

In still another embodiment, the methods comprise the steps of:

treating a compound having the formula

to form a first reaction product having the formula

reacting the first reaction product with a compound having the formula

to form a second reaction product having the formula

and

treating the second reaction product to form a third reaction producthaving the formula

-   -   wherein    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₆ is -L₁-R₂₂;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   or any two R₅, R₆ and R₇ are taken together to form a        substituted or unsubstituted ring;    -   X₅ is selected from the group consisting of CR₉R₁₀, CO, CS,        C(NR₁₁), NR₁₂, S and O;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond;    -   Z is selected from the group consisting of CR₁₄R₁₅, NR₁₆, O and        S;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur; and    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In yet another embodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

NHR₂₇R₂₈

to form a first reaction product having the formula

reacting the first reaction product with a compound having the formula

to form a second reaction product having the formula

and

reacting the second reaction product with a compound having the formula

to form a third reaction product having the formula

-   -   wherein    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₆ is -L₁-R₂₂;    -   or R₅ and R₆ are taken together to form a substituted or        unsubstituted ring;    -   X₅ and X₆ are each independently selected from the group        consisting of CR₉R₁₀, CO, CS, C(NR₁₁), NR₁₂, S and O;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond;    -   Z is selected from the group consisting of CR₁₄R₁₅, NR₁₆, O and        S;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈;    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring; and    -   G₂ and G₃ are each independently a leaving group.

In a further embodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

to form a first reaction product having the formula

treating the first reaction product to form a second reaction producthaving the formula

reacting the second reaction product with a compound having the formula

to form a third reaction product having the formula

and

reacting the third reaction product with a compound having the formula

NHR₁R₂

to form a fourth reaction product having the formula

-   -   wherein    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   or R₅ and R₇ are taken together to form a substituted or        unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈;    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring; and    -   G₂ and G₆ are each independently a leaving group.

In still a further embodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

to form a first reaction product having the formula

reacting the first reaction product with a compound having the formula

to form a second reaction product having the formula

and

reacting the second reaction product with a compound having the formula

NHR₁R₂

to form a third reaction product having the formula

-   -   wherein    -   X₁ and X₂ are each independently selected from the group        consisting of CR₉R₁₀, CO, CS, C(NR₁₁), NR₁₂, S and O;    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond,    -   or any two R₇, R₉, R₁₀, R₁₁ and R₁₂ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈;    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring; and    -   G₂ and G₄ are each independently a leaving group.

In yet a further embodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

to form a first reaction product having the formula

reacting the first reaction product with a compound having the formula

to form a second reaction product having the formula

reacting the second reaction product with a compound having the formula

NHR₁R₂

to form a third reaction product having the formula

and

treating the third reaction product to form a fourth reaction producthaving the formula

-   -   wherein    -   X₁ and X₂ are each independently selected from the group        consisting of CR₉R₁₀, CO, CS, C(NR₁₁), NR₁₂, S and O;    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond,    -   or any two R₇, R₉, R₁₀, R₁₁ and R₁₂ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and the ring to which L is attached, wherein the        atoms of the linker providing the separation are selected from        the group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈;    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring;    -   G₂ and G₄ are each independently a leaving group; and    -   G₅ is a protecting group.

In another embodiment, the methods comprise the step of:

treating a first reaction product having the formula

under conditions sufficient to form a second reaction product having theformula

-   -   wherein    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₆ is -L₁-R₂₂;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   or any two R₅, R₆ and R₇ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In one variation of the above embodiment, the methods further comprisethe step of:

reacting a compound having the formula

with a compound having the formula

to form the first reaction, wherein G₂ is a leaving group.

In another variation of the above embodiment and variation, the methodsfurther comprise the step of:

reacting the second reaction product with a compound having the formula

NHR₁R₂

to form a third reaction product having the formula

-   -   wherein    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;        and    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo.

In still another embodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

to form a first reaction product having the formula

treating the first reaction product under conditions sufficient to forma second reaction product having the formula

reacting the second reaction product with a compound having the formula

to form a third reaction product having the formula

reacting the third reaction product with a compound having the formula

to form a fourth reaction product having the formula

and

reacting the fourth reaction product with a compound having the formula

NHR₁R₂

to form a fifth reaction product having the formula

-   -   wherein    -   X₁, X₂ and X₃ are each independently selected from the group        consisting of CR₉R₁₀, CO, CS, C(NR₁₁), NR₁₂, S and O;    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond,    -   or any two R₉, R₁₀, R₁₁ and R₁₂ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈;    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring; and    -   G₂ and G₄ are each independently a leaving group.

In yet another embodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

to form a first reaction product having the formula

treating the first reaction product under conditions sufficient to forma second reaction product having the formula

treating the second reaction product under conditions sufficient to forma third reaction product having the formula

reacting the third reaction product with a compound having the formula

to form a fourth reaction product having the formula

reacting the fourth reaction product with a compound having the formula

to form a fifth reaction product having the formula

and

reacting the fifth reaction product with a compound having the formula

NHR₁R₂

to form a sixth reaction product having the formula

-   -   wherein    -   X₁ and X₂ are each independently selected from the group        consisting of CR₉R₁₀, CO, CS, C(NR₁₁), NR₁₂, S and O;    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₈ is -L₁-R₂₂, or two R₈ are taken together to form a        substituted or unsubstituted ring;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond,    -   or any two R₉, R₁₀, R₁₁ and R₁₂ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈;    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring;    -   G₂ is a leaving group; and    -   G₅ is a protecting group.

In still another of its aspects, the present invention relates tointermediates that are useful in making glucokinase activators. In oneembodiment, the intermediates comprise:

-   -   wherein    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₆ is -L₁-R₂₂;    -   or R₅ and R₆ are taken together to form a substituted or        unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In another embodiment, the intermediates comprise:

-   -   wherein    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₆ is -L₁-R₂₂;    -   or R₅ and R₆ are taken together to form a substituted or        unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In still another embodiment, the intermediates comprise:

-   -   wherein    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   or R₅ and R₇ are taken together to form a substituted or        unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In yet another embodiment, the intermediates comprise:

-   -   wherein    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   or R₅ and R₇ are taken together to form a substituted or        unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In a further embodiment, the intermediates comprise:

-   -   wherein    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₆ is -L₁-R₂₂;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   or any two R₅, R₆ and R₇ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In still a further embodiment, the intermediates comprise:

-   -   wherein    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₆ is -L₁-R₂₂;    -   or R₅ and R₆ are taken together to form a substituted or        unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In yet a further embodiment, the intermediates comprise:

-   -   wherein    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   or R₅ and R₇ are taken together to form a substituted or        unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In another embodiment, the intermediates comprise:

-   -   wherein    -   X₁ and X₂ are each independently selected from the group        consisting of CR₉R₁₀, CO, CS, C(NR₁₁), NR₁₂, S and O;    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond,    -   or any two R₇, R₉, R₁₀, R₁₁ and R₁₂ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈;    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring; and    -   G₄ is a leaving group.

In still another embodiment, the intermediates comprise:

-   -   wherein    -   X₁ and X₂ are each independently selected from the group        consisting of CR₉R₁₀, CO, CS, C(NR₁₁), NR₁₂, S and O;    -   R₃ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ is -L-R₁₈;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond,    -   or any two R₇, R₉, R₁₀, R₁₁ and R₁₂ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In yet another embodiment, the intermediates comprise:

-   -   wherein    -   X₁ and X₂ are each independently selected from the group        consisting of CR₉R₁₀, CO, CS, C(NR₁₁), NR₁₂, S and O;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond,    -   or any two R₇, R₉, R₁₀, R₁₁ and R₁₂ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and the ring to which L is attached, wherein the        atoms of the linker providing the separation are selected from        the group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈;    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring;    -   G₄ is a leaving group; and    -   G₅ is a protecting group.

In a further embodiment, the intermediates comprise:

-   -   wherein    -   X₁ and X₂ are each independently selected from the group        consisting of CR₉R₁₀, CO, CS, C(NR₁₁), NR₁₂, S and O;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond,    -   or any two R₇, R₉, R₁₀, R₁₁ and R₁₂ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and the ring to which L is attached, wherein the        atoms of the linker providing the separation are selected from        the group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈;    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring; and    -   G₅ is a protecting group.

In still a further embodiment, the intermediates comprise:

-   -   wherein    -   X₁ and X₂ are each independently selected from the group        consisting of CR₉R₁₀, CO, CS, C(NR₁₁), NR₁₂, S and O;    -   R₁ is selected from the group consisting of        hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, heteroaryl,        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and a        substituent convertible to hydrogen in vivo;    -   R₄ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₃ and R₄ are taken together to form a substituted or        unsubstituted ring;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ is -L₁-R₂₂;    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        to form oxo, with the proviso that R₁₀ is absent when the atom        to which it is bound forms part of a double bond;    -   R₁₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, with the proviso that R₁₂ is        absent when the atom to which it is bound forms part of a double        bond,    -   or any two R₇, R₉, R₁₀, R₁₁ and R₁₂ are taken together to form a        substituted or unsubstituted ring;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and the ring to which L is attached, wherein the        atoms of the linker providing the separation are selected from        the group consisting of carbon, oxygen, nitrogen, and sulfur;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈;    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring; and    -   G₅ is a protecting group.

In one variation of each of the above embodiments and variationscontaining R₁, R₁ is a substituted or unsubstituted heteroaryl. Inanother variation of each of the above embodiments and variationscontaining R₁, R₁ is selected from the group consisting of thiazolyl,pyrazinyl, pyrazolyl and pyridyl, each substituted or unsubstituted. Instill another variation of each of the above embodiments and variationscontaining R₁, R₁ is selected from the group consisting of thiazol-2-yl;2-pyridyl; 5-methyl-thiazol-2-yl; 6-methyl-pyrid-2-yl;4-methyl-pyrid-2-yl; 5-bromo-6-methyl-pyrid-2-yl; 5-phenyl-pyrid-2-yl;benzothiazol-2-yl; a nictoinic acid methyl ester; and5-bromo-pyrid-2-yl. In a further variation of each of the aboveembodiments and variations containing R₁, R₁ is a substituted orunsubstituted 2-pyrazinyl. In still a further variation of each of theabove embodiments and variations containing R₁, R₁ is a substituted orunsubstituted 1-methyl-pyrazol-3-yl. In yet a further variation of eachof the above embodiments and variations containing R₁, R₁ is asubstituted or unsubstituted 5-fluoro-thiazol-2-yl.

In yet another variation of each of the above embodiments and variationscontaining R₁, R₁ comprises:

-   -   wherein    -   q is selected from the group consisting of 3, 4 and 5;    -   each X is independently selected from the group consisting of        CR₁₄R₁₅, CO, CS, NR₁₆, O, S, SO and SO₂;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In a further variation of each of the above embodiments and variationscontaining R₁, R₁ comprises:

-   -   wherein    -   X₅, X₆ and X₇ are each independently selected from the group        consisting of CR₁₄R₁₅, CO, CS, NR₁₆, O, S, SO and SO₂;    -   Z is selected from the group consisting of CR₁₄R₁₅, NR₁₆, O and        S;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In another variation of each of the above embodiments and variationscontaining R₁, R₁ comprises:

-   -   wherein    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂.

In still a further variation of each of the above embodiments andvariations containing R₁, R₁ comprises:

-   -   wherein    -   X₅ and X₆ are each independently selected from the group        consisting of CR₁₄R₁₅, CO, CS, NR₁₆, O, S, SO and SO₂;    -   Z is selected from the group consisting of CR₁₄R₁₅, NR₁₆, O and        S;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₅ is absent when the atom to which it is        bound forms part of a double bond;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        with the proviso that R₁₆ is absent when the atom to which it is        bound forms part of a double bond,    -   or any two R₁₄, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In yet a further variation of each of the above embodiments andvariations containing R₁, R₁ comprises:

-   -   wherein    -   t is selected from the group consisting of 0, 1 and 2; and    -   each R₁₄ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        carboxamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂, or two R₁₄ are taken together to form a        substituted or unsubstituted ring;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In another variation of each of the above embodiments and variationscontaining R₁, R₁ comprises:

-   -   wherein    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In a further variation of each of the above embodiments and variationscontaining R₁, R₁ comprises:

-   -   wherein    -   t is selected from the group consisting of 0, 1 and 2; and    -   each R₁₄ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        carboxamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂, or two R₁₄ are taken together to form a        substituted or unsubstituted ring;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In still a further variation of each of the above embodiments andvariations containing R₁, R₁ comprises:

-   -   wherein    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In yet another variation of each of the above embodiments and variationscontaining R₁, R₁ comprises:

-   -   wherein    -   l is selected from the group consisting of 1 and 2;    -   r is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7 and 8;    -   W is selected from the group consisting of CR₁₇ or N;    -   each R₁₄ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        carboxamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂, or two R₁₄ are taken together to form a        substituted or unsubstituted ring;    -   R₁₇ is selected from the group consisting of hydrogen, halo,        (C₁₋₃)alkyl, aryl and heteroaryl, each substituted or        unsubstituted, or R₁₇ and R₁₄ are taken together to form a ring,        with the proviso that R₁₇ is absent when the atom to which it is        attached forms part of a double bond;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In one variation of the above variations containing W, W is CR₁₇. Inanother variation of the above variations containing W, W is N.

In another variation of each of the above embodiments and variationscontaining R₁, R₁ comprises:

-   -   wherein    -   n is selected from the group consisting of 0, 1, 2, 3 and 4;    -   each R₁₄ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        carboxamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₁₄ is -L₁-R₂₂, or two R₁₄ are taken together to form a        substituted or unsubstituted ring;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In yet another variation of each of the above embodiments and variationscontaining ring A, ring A is a substituted or unsubstituted heteroaryl.In a further variation of each of the above embodiments and variationscontaining ring A, ring A is selected from the group consisting ofthiazolyl, pyrazinyl, pyrazolyl and pyridyl, each substituted orunsubstituted. In a further variation of each of the above embodimentsand variations containing A, A is a substituted or unsubstituted2-pyrazinyl. In still a further variation of each of the aboveembodiments and variations containing A, A is a substituted orunsubstituted 1-methyl-pyrazol-3-yl. In yet a further variation of eachof the above embodiments and variations containing A, A is a substitutedor unsubstituted 5-fluoro-thiazol-2-yl.

In still a further variation of each of the above embodiments andvariations containing Z, Z is S.

In yet a further variation of each of the above embodiments andvariations containing X₁, X₁ is —CH═. In yet another variation of eachof the above embodiments and variations containing X₁, X₁ is —N═.

In another variation of each of the above embodiments and variationscontaining X₂, X₂ is —CH═. In yet another variation of each of the aboveembodiments and variations containing X₂, X₂ is —N═.

In a further variation of each of the above embodiments and variationscontaining X₃, X₃ is —CR₉=. In still another variation of each of theabove embodiments and variations containing X₃, X₃ is —CH═.

In a further variation of each of the above embodiments and variationscontaining X₄, X₄ is —CR₉═. In still another variation of each of theabove embodiments and variations containing X₄, X₄ is —CH═.

In a further variation of each of the above embodiments and variationscontaining X₁, X₂, X₃ and X₄, X₁ is —CH═, X₂ is —N═, X₃ is —CH═ and X₄is —CR₉═. In still a further variation of each of the above embodimentsand variations containing X₁, X₂, X₃ and X₄, X₁ is —CH═, X₂ is —CH═, X₃is —CR₉═ and X₄ is —CR₉═.

In still another variation of each of the above embodiments andvariations containing X₅, X₅ is —CH═.

In still another variation of each of the above embodiments andvariations containing X₆, X₆ is —CH═.

In still another variation of each of the above embodiments andvariations containing X₇, X₇ is —CH═. In a further variation of each ofthe above embodiments and variations containing X₇, X₇ is —N═.

In yet another variation of each of the above embodiments and variationscontaining R₂, R₂ is hydrogen.

In a further variation of each of the above embodiments and variationscontaining R₃,

-   -   R₃ is -L-R₁₈;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and R₁₈ to which L is attached, wherein the atoms        of the linker providing the separation are selected from the        group consisting of carbon, oxygen, nitrogen, and sulfur; and    -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still a further variation of each of the above embodiments andvariations containing R₃, R₃ comprises:

-   -   wherein    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and the ring to which L is attached, wherein the        atoms of the linker providing the separation are selected from        the group consisting of carbon, oxygen, nitrogen, and sulfur;    -   Q is selected from the group consisting of O, S, CS, CO, SO,        SO₂, CR₁₉R₂₀ and NR₂₁;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring;    -   R₁₉ and R₂₀ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;        and    -   R₂₁ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet a further variation of each of the above embodiments andvariations containing R₃, R₃ comprises:

-   -   wherein    -   m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8, 9, 10 and 11;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and the ring to which L is attached, wherein the        atoms of the linker providing the separation are selected from        the group consisting of carbon, oxygen, nitrogen, and sulfur;        and    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring.

In another variation of each of the above embodiments and variationscontaining R₃, R₃ comprises:

-   -   wherein    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and the ring to which L is attached, wherein the        atoms of the linker providing the separation are selected from        the group consisting of carbon, oxygen, nitrogen, and sulfur;        and    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring.

In still another variation of each of the above embodiments andvariations containing R₃, R₃ comprises:

-   -   wherein    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and the ring to which L is attached, wherein the        atoms of the linker providing the separation are selected from        the group consisting of carbon, oxygen, nitrogen, and sulfur;        and    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring.

In yet another variation of each of the above embodiments and variationscontaining R₃, R₃ is selected from the group consisting of (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted.

In a further variation of each of the above embodiments and variationscontaining R₃, R₃ comprises:

-   -   wherein    -   p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7, 8 and 9;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and the ring to which L is attached, wherein the        atoms of the linker providing the separation are selected from        the group consisting of carbon, oxygen, nitrogen, and sulfur;        and    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring.

In still a further variation of each of the above embodiments andvariations containing R₃, R₃ comprises:

-   -   wherein    -   p′ is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6        and 7;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and the ring to which L is attached, wherein the        atoms of the linker providing the separation are selected from        the group consisting of carbon, oxygen, nitrogen, and sulfur;        and    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or two R₁₃ are taken together to form a substituted or        unsubstituted ring.

In yet a further variation of each of the above embodiments andvariations containing R₃, R₃ comprises:

-   -   wherein    -   Q is selected from the group consisting of O, S, CS, CO, SO,        SO₂, CR₁₉R₂₀ and NR₂₁;    -   L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation        between the C and the ring to which L is attached, wherein the        atoms of the linker providing the separation are selected from        the group consisting of carbon, oxygen, nitrogen, and sulfur;    -   R₁₉ and R₂₀ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;        and    -   R₂₁ is selected from the group consisting of hydrogen, hydroxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another variation of each of the above embodiments and variationscontaining R₃, R₃ is selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, and heteroaryl(C₁₋₅)alkyl, each substituted orunsubstituted. In still another variation of each of the aboveembodiments and variations containing R₃, R₃ is selected from the groupconsisting of butyl; hexylmethyl; benzyl; imidazol-4-ylmethyl, phenyland (tetrahydro-2H-pyran-4-yl)methyl. In yet another variation of eachof the above embodiments and variations containing R₃, R₃ is asubstituted or unsubstituted (tetrahydro-2H-pyran-4-yl)methyl. In afurther variation of each of the above embodiments and variationscontaining R₃, R₃ is selected from the group consisting of butyl;hexylmethyl; benzyl; imidazol-4-ylmethyl and phenyl. In still a furthervariation of each of the above embodiments and variations containing R₃,R₃ is selected from the group consisting of alkyl, cycloalkyl-alkyl,dihaloaryl-alkyl, alkoxyaryl-alkyl, alkoxycycloalkyl-alkyl,tetrahydrofuranyl-alkyl, furanyl-alkyl and tetrahydro-2H-pyranyl-alky,each substituted or unsubstituted.

In yet a further variation of each of the above embodiments andvariations containing L, L is —CH₂—. In another variation of each of theabove embodiments and variations containing L, L is selected from thegroup consisting of —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂C(O)—,—CH₂—C(O)CH₂—, —CH₂CH₂C(O)—, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —CH₂NH—,—CH₂NHCH₂—, —CH₂CH₂NH—, —CH₂NHC(O)—, —CH₂C(O)NH—, —CH₂S—, —CH₂SCH₂—,—CH₂CH₂S—, —CH₂C(O)S— and —CH₂SC(O)—, each substituted or unsubstituted.In still another variation of each of the above embodiments andvariations containing L, L is selected from the group consisting of—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —C(O)—, —CH₂C(O)—, —C(O)CH₂—,—CH₂—C(O)CH₂—, —C(O)CH₂CH₂—, —CH₂CH₂C(O)—, —O—, —OCH₂—, —CH₂O—,—CH₂OCH₂—, —OCH₂CH₂—, —CH₂CH₂O—, —N(CH₃)—, —NHCH₂—, —CH₂NH—, —CH₂NHCH₂—,—NHCH₂CH₂—, —CH₂CH₂NH—, —NH—C(O)—, —NCH₃—C(O)—, —C(O)NH—, —C(O)NCH₃—,—NHC(O)CH₂—, —C(O)NHCH₂—, —C(O)CH₂NH—, —CH₂NHC(O)—, —CH₂C(O)NH—,—NHCH₂C(O)—, —S—, —SCH₂—, —CH₂S—, —SCH₂CH₂—, —CH₂SCH₂—, —CH₂CH₂S—,—C(O)S—, —C(O)SCH₂—, —CH₂C(O)S—, —C(O)CH₂S—, and —CH₂SC(O)—, eachsubstituted or unsubstituted.

In yet another variation of each of the above embodiments and variationscontaining L,

-   -   L is selected from the group consisting of —(CR₂₄R₂₅)_(s)—;    -   s is selected from the group consisting from the group        consisting of 1, 2, 3, 4, 5 and 6; and    -   R₂₄ and R₂₅ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In a further variation of each of the above embodiments and variationscontaining Q, Q is —CR₁₉R₂₀—. In still a further variation of each ofthe above embodiments and variations containing Q, Q is —CH₂—. In yet afurther variation of each of the above embodiments and variationscontaining Q, Q is —NR₂₁—. In another variation of each of the aboveembodiments and variations containing Q, Q is —NH—. In a furthervariation of each of the above embodiments and variations containing Q,Q is —O—.

In still another variation of each of the above embodiments andvariations containing R₄, R₄ is selected from the group consisting ofcarbonyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted.

In yet another variation of each of the above embodiments and variationscontaining R₄, R₄ is selected from the group consisting of hydrogen,(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl, andheteroaryl(C₁₋₅)alkyl, each substituted or unsubstituted. In a furthervariation of each of the above embodiments and variations containing R₄,R₄ is selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, and heteroaryl(C₁₋₅)alkyl, each substituted orunsubstituted. In still a further variation of each of the aboveembodiments and variations containing R₄, R₄ is selected from the groupconsisting of hydrogen; butyl; cyclohexylmethyl; benzyl;imidazol-4-ylmethyl and phenyl. In yet a further variation of each ofthe above embodiments and variations containing R₄, R₄ is selected fromthe group consisting of butyl; cyclohexylmethyl; benzyl;imidazol-4-ylmethyl and phenyl. In another variation of each of theabove embodiments and variations containing R₄, R₄ is hydrogen.

In still another variation of each of the above embodiments andvariations containing R₅, R₅ is hydrogen. In yet another variation ofeach of the above embodiments and variations containing R₅, R₅ is halo.In a further variation of each of the above embodiments and variationscontaining R₅, R₅ is a substituted or unsubstituted (C₁₋₃)alkyl.

In still a further variation of each of the above embodiments andvariations containing R₆, R₆ is hydrogen. In yet a further variation ofeach of the above embodiments and variations containing R₆, R₆ is halo.In another variation of each of the above embodiments and variationscontaining R₆, R₆ is a substituted or unsubstituted (C₁₋₃)alkyl. Instill another variation of each of the above embodiments and variationscontaining R₆, R₆ is a substituted or unsubstituted (C₁₋₃)alkylsulfonyl.In yet another variation of each of the above embodiments and variationscontaining R₆, R₆ is a substituted or unsubstituted(C₁₋₆)cycloalkylsulfonyl. In yet a further variation of each of theabove embodiments and variations containing R₆, R₆ is selected from thegroup consisting of methylsulfonyl, cyclopropylsulfonyl andcyclopentylsulfonyl, each substituted or unsubstituted.

In another variation of each of the above embodiments and variationscontaining R₆,

-   -   R₆ is -L₁-R₂₂;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In still another variation of each of the above embodiments andvariations containing R₆, R₆ is —SO₂—R₂₂; R₂₂ is selected from the groupconsisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ areeach independently selected from the group consisting of hydrogen,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.

In yet another variation of each of the above embodiments and variationscontaining R₆, R₆ is —CO—R₂₂; R₂₂ is selected from the group consistingof hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.

In a further variation of each of the above embodiments and variationscontaining R₆, R₆ is —NH—SO₂—R₂₂; R₂₂ is selected from the groupconsisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ areeach independently selected from the group consisting of hydrogen,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.

In still a further variation of each of the above embodiments andvariations containing R₆, R₆ is —NH—CO—R₂₂; R₂₂ is selected from thegroup consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ areeach independently selected from the group consisting of hydrogen,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.

In yet a further variation of each of the above embodiments andvariations containing R₆, R₆ is —CO—NH—R₂₂; R₂₂ is selected from thegroup consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ areeach independently selected from the group consisting of hydrogen,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.

In another variation of each of the above embodiments and variationscontaining R₇, R₇ is hydrogen. In still another variation of each of theabove embodiments and variations containing R₇, R₇ is halo. In yetanother variation of each of the above embodiments and variationscontaining R₇, R₇ is a substituted or unsubstituted (C₁₋₃)alkyl.

In a further variation of each of the above embodiments and variationscontaining R₇,

-   -   R₇ is -L₁-R₂₂;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In a further variation of each of the above embodiments and variationscontaining R₇, R₇ is —CO—R₂₂; R₂₂ is selected from the group consistingof hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.

In still a further variation of each of the above embodiments andvariations containing R₇, R₇ is —NH—SO₂—R₂₂; R₂₂ is selected from thegroup consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ areeach independently selected from the group consisting of hydrogen,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.

In yet a further variation of each of the above embodiments andvariations containing R₅ and R₆, R₅ and R₆, together with the atoms towhich they are attached, form a substituted or unsubstituted aryl. Inanother variation of each of the above embodiments and variationscontaining R₅ and R₆, R₅ and R₆, together with the atoms to which theyare attached, form a substituted or unsubstituted phenyl. In stillanother variation of each of the above embodiments and variationscontaining R₅ and R₆, R₅ and R₆, together with the atoms to which theyare attached, form a substituted or unsubstituted heteroaryl.

In yet another variation of each of the above embodiments and variationscontaining R₆ and R₇, R₆ and R₇, together with the atoms to which theyare attached, form a substituted or unsubstituted aryl. In a furthervariation of each of the above embodiments and variations containing R₆and R₇, R₆ and R₇, together with the atoms to which they are attached,form a substituted or unsubstituted phenyl. In still a further variationof each of the above embodiments and variations containing R₆ and R₇, R₆and R₇, together with the atoms to which they are attached, form asubstituted or unsubstituted heteroaryl.

In yet a further variation of each of the above embodiments andvariations containing R₈, R₈ is hydrogen. In another variation of eachof the above embodiments and variations containing R₈, R₈ is halo. Inanother variation of each of the above embodiments and variationscontaining R₈, R₈ is a substituted or unsubstituted (C₁₋₃)alkyl. Instill another variation of each of the above embodiments and variationscontaining R₈, R₈ is a substituted or unsubstituted sulfonyl(C₁₋₃)alkyl.In a further variation of each of the above embodiments and variationscontaining R₈, R₈ is a substituted or unsubstituted (C₁₋₃)alkylsulfonyl.In still a further variation of each of the above embodiments andvariations containing R₈, R₈ is a substituted or unsubstituted(C₃₋₁₂)cycloalkylsulfonyl. In yet another variation of each of the aboveembodiments and variations containing R₈, R₈ is selected from the groupconsisting of sulfonylmethyl, methylsulfonyl, cyclopropylsulfonyl andcyclopentylsulfonyl, each substituted or unsubstituted. In a furthervariation of each of the above embodiments and variations containing R₈,R₈ is a substituted or unsubstituted cyclopropylsulfonyl. In still afurther variation of each of the above embodiments and variationscontaining R₈, R₈ is cyano. In yet a further variation of each of theabove embodiments and variations containing R₈, R₈ is a substituted orunsubstituted (C₁₋₆)alkoxy. In another variation of each of the aboveembodiments and variations containing R₈, R₈ is methoxy.

In a further variation of each of the above embodiments and variationscontaining R₈,

-   -   R₈ is -L₁-R₂₂;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₂ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In still a further variation of each of the above embodiments andvariations containing R₈, R₈ is —SO₂—R₂₂; R₂₂ is selected from the groupconsisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ areeach independently selected from the group consisting of hydrogen,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.

In yet a further variation of each of the above embodiments andvariations containing R₈, R₈ is —CO—R₂₂; R₂₂ is selected from the groupconsisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ areeach independently selected from the group consisting of hydrogen,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.

In another variation of each of the above embodiments and variationscontaining R₈, R₈ is —NH—SO₂—R₂₂; R₂₂ is selected from the groupconsisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ areeach independently selected from the group consisting of hydrogen,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.

In still another variation of each of the above embodiments andvariations containing R₈, R₈ is —NH—CO—R₂₂; R₂₂ is selected from thegroup consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ areeach independently selected from the group consisting of hydrogen,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.

In yet another variation of each of the above embodiments and variationscontaining R₈, R₈ is —CO—NH—R₂₂; R₂₂ is selected from the groupconsisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ areeach independently selected from the group consisting of hydrogen,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.

In a further variation of each of the above embodiments and variationscontaining R₃ and R₈, R₃ is a substituted or unsubstituted(tetrahydro-2H-pyran-4-yl)methyl and R₈ is a substituted orunsubstituted cyclopropylsulfonyl.

In another variation of each of the above embodiments and variationscontaining R₉, R₉ is a substituted or unsubstituted cyclopropylsulfonyl.In still another variation of each of the above embodiments andvariations containing R₉, R₉ is a substituted or unsubstituted(C₁₋₃)alkoxy. In yet another variation of each of the above embodimentsand variations containing R₉, R₉ is methoxy.

In still a further variation of each of the above embodiments andvariations containing R₃ and R₉, R₃ is a substituted or unsubstituted(tetrahydro-2H-pyran-4-yl)methyl and R₉ is a substituted orunsubstituted cyclopropylsulfonyl.

In still another variation of each of the above embodiments andvariations containing R₁₀, R₁₀ is hydrogen. In yet another variation ofeach of the above embodiments and variations containing R₁₀, R₁₀ ishalo. In a further variation of each of the above embodiments andvariations containing R₁₀, R₁₀ is a substituted or unsubstituted(C₁₋₃)alkyl.

In still another variation of each of the above embodiments andvariations containing R₁₁, R₁₁ is hydrogen. In a further variation ofeach of the above embodiments and variations containing R₁₁, R₁₁ is asubstituted or unsubstituted (C₁₋₃)alkyl.

In still another variation of each of the above embodiments andvariations containing R₁₂, R₁₂ is hydrogen. In a further variation ofeach of the above embodiments and variations containing R₁₂, R₁₂ is asubstituted or unsubstituted (C₁₋₃)alkyl.

In still another variation of each of the above embodiments andvariations containing R₁₃, R₁₃ is hydrogen. In yet another variation ofeach of the above embodiments and variations containing R₁₃, R₁₃ ishalo. In a further variation of each of the above embodiments andvariations containing R₁₃, R₁₃ is a substituted or unsubstituted(C₁₋₃)alkyl.

In another variation of each of the above embodiments and variationscontaining R₁₄, each R₁₄ is independently selected from the groupconsisting of hydrogen, halo, a substituted or unsubstituted (C₁₋₅)alkyland a substituted or unsubstituted carboxamido. In a further variationof each of the above embodiments and variations containing R₁₄, at leastone R₁₄ is a substituted or unsubstituted carboxamido. In still afurther variation of each of the above embodiments and variationscontaining R₁₄, at least one R₁₄ is hydrogen. In yet a further variationof each of the above embodiments and variations containing R₁₄, at leastone R₁₄ is halo. In another variation of each of the above embodimentsand variations containing R₁₄, at least one R₁₄ is fluoro. In stillanother variation of each of the above embodiments and variationscontaining R₁₄, at least one R₁₄ is chloro. In another variation of eachof the above embodiments and variations containing R₁₄, at least one R₁₄is a substituted or unsubstituted (C₁₋₅)alkyl. In another variation ofeach of the above embodiments and variations containing R₁₄, at leastone R₁₄ is methyl. In still another variation of each of the aboveembodiments and variations containing R₁₄, two R₁₄, together with theatoms to which they are attached, are taken together to form asubstituted or unsubstituted ring.

In still another variation of each of the above embodiments andvariations containing R₁₄, R₁₄ is oxa(C₁₋₅)alkyl. In yet anothervariation of each of the above embodiments and variations containingR₁₄, R₁₄ is oxo(C₁₋₅)alkyl. In a further variation of each of the aboveembodiments and variations containing R₁₄, R₁₄ is -L₁-R₂₂, where L₁ isabsent or a linker providing 1, 2, 3, 4, 5 or 6 atom separation betweenR₂₂ and the ring to which L₁ is attached, wherein the atoms of thelinker providing the separation are selected from the group consistingof carbon, oxygen, nitrogen, and sulfur; R₂₂ is selected from the groupconsisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ areeach independently selected from the group consisting of hydrogen,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.

In still a further variation of each of the above embodiments andvariations containing R₁₄, R₁₄ is selected from the group consisting ofhydrogen, halo, cyano, —OR₂₂, —SO₂—R₂₂, —NH—SO₂—R₂₂ and —SO₂—NH—R₂₂; R₂₂is selected from the group consisting of hydrogen, halo, nitro, cyano,thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ areeach independently selected from the group consisting of hydrogen,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring. In yet a further variation of eachof the above embodiments and variations containing R₁₄, R₁₄ is selectedfrom the group consisting of halo, (C₁₋₅)alkyl, oxa(C₁₋₅)alkyl andoxo(C₁₋₅)alkyl, each substituted or unsubstituted.

In yet another variation of each of the above embodiments and variationscontaining R₁₅, R₁₅ is hydrogen. In a further variation of each of theabove embodiments and variations containing R₁₅, R₁₅ is halo. In yet afurther variation of each of the above embodiments and variationscontaining R₁₅, R₁₅ is a substituted or unsubstituted (C₁₋₅)alkyl.

In a further variation of each of the above embodiments and variationscontaining R₁₆, R₁₆ is (C₁₋₅)alkyl. In another variation of each of theabove embodiments and variations containing R₁₆, R₁₆ is methyl.

In another variation of each of the above embodiments and variationscontaining R₁₇, R₁₇ is absent. In still another variation of each of theabove embodiments and variations containing R₁₇, R₁₇ is hydrogen. In yetanother variation of each of the above embodiments and variationscontaining R₁₇, R₁₇ is (C₁₃)alkyl. In another variation of each of theabove embodiments and variations containing R₁₇, R₁₇ is methyl. In afurther variation of each of the above embodiments and variationscontaining R₁₇, R₁₇ is halo.

In another variation of each of the above embodiments and variationscontaining R₁₈, R₁₈ is selected from the group consisting of alkyl,cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each substituted orunsubstituted.

In still another variation of each of the above embodiments andvariations containing R₁₉, R₁₉ is hydrogen. In yet another variation ofeach of the above embodiments and variations containing R₁₉, R₁₉ ishalo. In a further variation of each of the above embodiments andvariations containing R₁₉, R₁₉ is a substituted or unsubstituted(C₁₋₃)alkyl.

In still another variation of each of the above embodiments andvariations containing R₂₀, R₂₀ is hydrogen. In yet another variation ofeach of the above embodiments and variations containing R₂₀, R₂₀ ishalo. In a further variation of each of the above embodiments andvariations containing R₂₀, R₂₀ is a substituted or unsubstituted(C₁₋₃)alkyl.

In still another variation of each of the above embodiments andvariations containing R₂₁, R₂₁ is hydrogen. In a further variation ofeach of the above embodiments and variations containing R₂₁, R₂₁ is asubstituted or unsubstituted (C₁₋₃)alkyl.

In still another variation of each of the above embodiments andvariations containing R₂₂, R₂₂ is a substituted or unsubstituted(C₁₋₅)alkyl. In yet another variation of each of the above embodimentsand variations containing R₂₂, R₂₂ is a substituted or unsubstituted(C₃₋₆)cycloalkyl. In a further variation of each of the aboveembodiments and variations containing R₂₂, R₂₂ is a substituted orunsubstituted (C₄₋₈)aryl. In still a further variation of each of theabove embodiments and variations containing R₂₂, R₂₂ is a substituted orunsubstituted phenyl. In yet a further variation of each of the aboveembodiments and variations containing R₂₂, R₂₂ is a substituted orunsubstituted hetero(C₁₋₆)aryl. In another variation of each of theabove embodiments and variations containing R₂₂, R₂₂ is cyclopropyl.

In still another variation of each of the above embodiments andvariations containing R₂₂,

-   -   R₂₂ is —NR₂₇R₂₈; and    -   R₂₇ and R₂₈ are each independently selected from the group        consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, aryl, heteroaryl, (C₉₋₁₂)bicycloaryl        and hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        or R₂₇ and R₂₈ are taken together to form a substituted or        unsubstituted ring.

In yet a further variation of each of the above embodiments andvariations containing L₁,

-   -   L₁ is selected from the group consisting of —(CR₂₄R₂₅)_(s)—,        —NR₂₆—, —O—, —S—, —CO—, —CS—, —SO—, —SO₂—, and combinations        thereof;    -   s is selected from the group consisting from the group        consisting of 1, 2, 3, 4, 5 and 6;    -   R₂₄ and R₂₅ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₆ is selected from the group consisting of hydrogen, cyano,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In another variation of each of the above embodiments and variationscontaining L₁, L₁ is —SO₂—. In still another variation of each of theabove embodiments and variations containing L₁, L₁ is —C(O)—NR₂₆— andR₂₆ is selected from the group consisting of hydrogen, cyano, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted.

In yet another variation of each of the above embodiments and variationscontaining L₁, L₁ is —C(S)—NR₂₆— and R₂₆ is selected from the groupconsisting of hydrogen, cyano, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido,amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₁₀)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted.

In a further variation of each of the above embodiments and variationscontaining R₂₄, R₂₄ is selected from the group consisting of H and asubstituted or unsubstituted (C₁₋₅)alkyl.

In still a further variation of each of the above embodiments andvariations containing R₂₅, R₂₅ is selected from the group consisting ofH and a substituted or unsubstituted (C₁₋₅)alkyl.

In yet a further variation of each of the above embodiments andvariations containing R₂₆, R₂₆ is selected from the group consisting ofhydrogen and a substituted or unsubstituted (C₁₋₁₀)alkyl.

In yet another variation of each of the above embodiments and variationscontaining R₂₇, R₂₇ is a substituted or unsubstituted (C₃₋₁₂)cycloalkyl.In a further variation of each of the above embodiments and variationscontaining R₂₇, R₂₇ is a substituted or unsubstituted cyclopropyl.

In still a further variation of each of the above embodiments andvariations containing R₂₈, R₂₈ is hydrogen.

In another variation of each of the above embodiments and variationscontaining l, l is 1.

In still another variation of each of the above embodiments andvariations containing m, m is 0. In yet another variation of each of theabove embodiments and variations containing m, m is 1. In a furthervariation of each of the above embodiments and variations containing m,m is 2.

In a further variation of each of the above embodiments and variationscontaining n, n is 0. In still a further variation of each of the aboveembodiments and variations containing n, n is 1. In yet a furthervariation of each of the above embodiments and variations containing n,n is 2.

In a further variation of each of the above embodiments and variationscontaining n′, n′ is 0. In still a further variation of each of theabove embodiments and variations containing n′, n′ is 1. In yet afurther variation of each of the above embodiments and variationscontaining n′, n′ is 2.

In a further variation of each of the above embodiments and variationscontaining n″, n″ is 0. In still a further variation of each of theabove embodiments and variations containing n″, n″ is 1. In yet afurther variation of each of the above embodiments and variationscontaining n″, n″ is 2.

In another variation of each of the above embodiments and variationscontaining p, p is 0. In still another variation of each of the aboveembodiments and variations containing p, p is 1. In yet anothervariation of each of the above embodiments and variations containing p,p is 2.

In another variation of each of the above embodiments and variationscontaining p′, p′ is 0. In still another variation of each of the aboveembodiments and variations containing p′, p′ is 1. In yet anothervariation of each of the above embodiments and variations containing p′,p′ is 2.

In a further variation of each of the above embodiments and variationscontaining q, q is 3. In still a further variation of each of the aboveembodiments and variations containing q, q is 4.

In another variation of each of the above embodiments and variationscontaining r, r is 1.

In a further variation of each of the above embodiments and variationscontaining s, s is 0. In still a further variation of each of the aboveembodiments and variations containing s, s is 1.

In another variation of each of the above embodiments and variationscontaining t, t is 1.

It is noted that the compounds of the present invention may be in theform of a pharmaceutically acceptable salt, biohydrolyzable ester,biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate orprodrug thereof. For example, the compound optionally comprises asubstituent that is convertible in vivo to a different substituent, suchas hydrogen. It is further noted that the compound may be present in amixture of stereoisomers, or the compound may comprise a singlestereoisomer.

The present invention also provides a pharmaceutical compositioncomprising as an active ingredient a compound according to any one ofthe above embodiments and variations. In one particular variation, thecomposition is a solid formulation adapted for oral administration. Inanother particular variation, the composition is a liquid formulationadapted for oral administration. In yet another particular variation,the composition is a tablet. In still another particular variation, thecomposition is a liquid formulation adapted for parenteraladministration.

In another of its aspects, there is provided a pharmaceuticalcomposition comprising a compound according to any one of the aboveembodiments and variations, wherein the composition is adapted foradministration by a route selected from the group consisting of orally,parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, and intrathecally.

In yet another of its aspects, there is provided a kit comprising acompound of any one of the above embodiments and variations; andinstructions which comprise one or more forms of information selectedfrom the group consisting of indicating a disease state for which thecomposition is to be administered, storage information for thecomposition, dosing information and instructions regarding how toadminister the composition. In one particular variation, the kitcomprises the compound in a multiple dose form.

In still another of its aspects, there is provided an article ofmanufacture comprising a compound of any one of the above embodimentsand variations; and packaging materials. In one variation, the packagingmaterial comprises a container for housing the compound. In oneparticular variation, the container comprises a label indicating one ormore members of the group consisting of a disease state for which thecompound is to be administered, storage information, dosing informationand/or instructions regarding how to administer the compound. In anothervariation, the article of manufacture comprises the compound in amultiple dose form.

In a further of its aspects, there is provided a therapeutic methodcomprising administering a compound of any one of the above embodimentsand variations to a subject.

In another of its aspects, there is provided a method of activatingglucokinase comprising contacting glucokinase with a compound of any oneof the above embodiments and variations.

In yet another of its aspects, there is provided a method of activatingglucokinase comprising causing a compound of any one of the aboveembodiments and variations to be present in a subject in order toactivate glucokinase in vivo.

In a further of its aspects, there is provided a method of activatingglucokinase comprising administering a first compound to a subject thatis converted in vivo to a second compound wherein the second compoundactivates glucokinase in vivo, the second compound being a compoundaccording to any one of the above embodiments and variations.

In another of its aspects, there is provided a method of treating adisease state for which increasing glucokinase activity ameliorates thepathology and/or symptomology of the disease state, the methodcomprising causing a compound of any one of the above embodiments andvariations to be present in a subject in a therapeutically effectiveamount for the disease state.

In yet another of its aspects, there is provided a method of treating adisease state for which increasing glucokinase activity ameliorates thepathology and/or symptomology of the disease state, the methodcomprising administering a compound of any one of the above embodimentsand variations to a subject, wherein the compound is present in thesubject in a therapeutically effective amount for the disease state.

In a further of its aspects, there is provided a method of treating adisease state for which increasing glucokinase activity ameliorates thepathology and/or symptomology of the disease state, the methodcomprising administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound activatesglucokinase in vivo, the second compound being a compound according toany one of the above embodiments and variations.

In one variation of each of the above methods the disease state isselected from the group consisting of hyperglycemia, diabetes,dyslipidaemia, obesity, insulin resistance, metabolic syndrome X,impaired glucose tolerance, polycystic ovary syndrome, andcardiovascular disease.

Salts, Hydrates, and Prodrugs of Glucokinase Activators

It should be recognized that the compounds of the present invention maybe present and optionally administered in the form of salts, hydratesand prodrugs that are converted in vivo into the compounds of thepresent invention. For example, it is within the scope of the presentinvention to convert the compounds of the present invention into and usethem in the form of their pharmaceutically acceptable salts derived fromvarious organic and inorganic acids and bases in accordance withprocedures well known in the art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydroiodide; othermineral acids and their corresponding salts such as sulfate, nitrate,phosphate, etc.; and alkyl and monoarylsulfonates such asethanesulfonate, toluenesulfonate and benzenesulfonate; and otherorganic acids and their corresponding salts such as acetate, tartrate,maleate, succinate, citrate, benzoate, salicylate and ascorbate. Furtheracid addition salts of the present invention include, but are notlimited to: adipate, alginate, arginate, aspartate, bisulfate,bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate,chloride, chlorobenzoate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate,galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate,glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate,lactobionate, malate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate and phthalate. It should be recognized that the free baseforms will typically differ from their respective salt forms somewhat inphysical properties such as solubility in polar solvents, but otherwisethe salts are equivalent to their respective free base forms for thepurposes of the present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base. Examples of such bases are alkalimetal hydroxides including potassium, sodium and lithium hydroxides;alkaline earth metal hydroxides such as barium and calcium hydroxides;alkali metal alkoxides, e.g., potassium ethanolate and sodiumpropanolate; and various organic bases such as ammonium hydroxide,piperidine, diethanolamine and N-methylglutamine. Also included are thealuminum salts of the compounds of the present invention. Further basesalts of the present invention include, but are not limited to: copper,ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,sodium and zinc salts. Organic base salts include, but are not limitedto, salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, e.g., arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine(benzathine),dicyclohexylamine, diethanolamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, iso-propylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine andtris-(hydroxymethyl)-methylamine(tromethamine). It should be recognizedthat the free acid forms will typically differ from their respectivesalt forms somewhat in physical properties such as solubility in polarsolvents, but otherwise the salts are equivalent to their respectivefree acid forms for the purposes of the present invention.

Compounds of the present invention that comprise basicnitrogen-containing groups may be quaternized with such agents as (C₁₋₄)alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides,bromides and iodides; di(C₁₋₄) alkyl sulfates, e.g., dimethyl, diethyland diamyl sulfates; (C₁₀₋₁₈) alkyl halides, e.g., decyl, dodecyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; andaryl(C₁₋₄) alkyl halides, e.g., benzyl chloride and phenethyl bromide.Such salts permit the preparation of both water-soluble and oil-solublecompounds of the present invention.

N-oxides of compounds according to the present invention can be preparedby methods known to those of ordinary skill in the art. For example,N-oxides can be prepared by treating an unoxidized form of the compoundwith an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid,perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or thelike) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethane) at approximately 0° C.Alternatively, the N-oxides of the compounds can be prepared from theN-oxide of an appropriate starting material.

Prodrug derivatives of compounds according to the present invention canbe prepared by modifying substituents of compounds of the presentinvention that are then converted in vivo to a different substituent. Itis noted that in many instances, the prodrugs themselves also fallwithin the scope of the range of compounds according to the presentinvention. For example, prodrugs can be prepared by reacting a compoundwith a carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like) or an acylating agent. Furtherexamples of methods of making prodrugs are described in Saulnier et al.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.

Protected derivatives of compounds of the present invention can also bemade. Examples of techniques applicable to the creation of protectinggroups and their removal can be found in T.W. Greene, Protecting Groupsin Organic Synthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds of the present invention may also be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

A “pharmaceutically acceptable salt”, as used herein, is intended toencompass any compound according to the present invention that isutilized in the form of a salt thereof, especially where the saltconfers on the compound improved pharmacokinetic properties as comparedto the free form of compound or a different salt form of the compound.The pharmaceutically acceptable salt form may also initially conferdesirable pharmacokinetic properties on the compound that it did notpreviously possess, and may even positively affect the pharmacodynamicsof the compound with respect to its therapeutic activity in the body. Anexample of a pharmacokinetic property that may be favorably affected isthe manner in which the compound is transported across cell membranes,which in turn may directly and positively affect the absorption,distribution, biotransformation and excretion of the compound. While theroute of administration of the pharmaceutical composition is important,and various anatomical, physiological and pathological factors cancritically affect bioavailability, the solubility of the compound isusually dependent upon the character of the particular salt formthereof, which it utilized. One of skill in the art will appreciate thatan aqueous solution of the compound will provide the most rapidabsorption of the compound into the body of a subject being treated,while lipid solutions and suspensions, as well as solid dosage forms,will result in less rapid absorption of the compound.

Compositions Comprising Glucokinase Activators

A wide variety of compositions and administration methods may be used inconjunction with the compounds of the present invention. Suchcompositions may include, in addition to the compounds of the presentinvention, conventional pharmaceutical excipients, and otherconventional, pharmaceutically inactive agents. Additionally, thecompositions may include active agents in addition to the compounds ofthe present invention. These additional active agents may includeadditional compounds according to the invention, and/or one or moreother pharmaceutically active agents.

The compositions may be in gaseous, liquid, semi-liquid or solid form,formulated in a manner suitable for the route of administration to beused. For oral administration, capsules and tablets are typically used.For parenteral administration, reconstitution of a lyophilized powder,prepared as described herein, is typically used.

Compositions comprising compounds of the present invention may beadministered or coadministered orally, parenterally, intraperitoneally,intravenously, intraarterially, transdermally, sublingually,intramuscularly, rectally, transbuccally, intranasally, liposomally, viainhalation, vaginally, intraoccularly, via local delivery (for exampleby catheter or stent), subcutaneously, intraadiposally,intraarticularly, or intrathecally. The compounds and/or compositionsaccording to the invention may also be administered or coadministered inslow release dosage forms.

The glucokinase activators and compositions comprising them may beadministered or coadministered in any conventional dosage form.Co-administration in the context of this invention is intended to meanthe administration of more than one therapeutic agent, one of whichincludes a glucokinase activator, in the course of a coordinatedtreatment to achieve an improved clinical outcome. Suchco-administration may also be coextensive, that is, occurring duringoverlapping periods of time.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application may optionally include one or more of thefollowing components: a sterile diluent, such as water for injection,saline solution, fixed oil, polyethylene glycol, glycerine, propyleneglycol or other synthetic solvent; antimicrobial agents, such as benzylalcohol and methyl parabens; antioxidants, such as ascorbic acid andsodium bisulfite; chelating agents, such as ethylenediaminetetraaceticacid (EDTA); buffers, such as acetates, citrates and phosphates; agentsfor the adjustment of tonicity such as sodium chloride or dextrose, andagents for adjusting the acidity or alkalinity of the composition, suchas alkaline or acidifying agents or buffers like carbonates,bicarbonates, phosphates, hydrochloric acid, and organic acids likeacetic and citric acid. Parenteral preparations may optionally beenclosed in ampules, disposable syringes or single or multiple dosevials made of glass, plastic or other suitable material.

When compounds according to the present invention exhibit insufficientsolubility, methods for solubilizing the compounds may be used. Suchmethods are known to those of skill in this art, and include, but arenot limited to, using cosolvents, such as dimethylsulfoxide (DMSO),using surfactants, such as TWEEN, or dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as prodrugs of thecompounds may also be used in formulating effective pharmaceuticalcompositions.

Upon mixing or adding compounds according to the present invention to acomposition, a solution, suspension, emulsion or the like may be formed.The form of the resulting composition will depend upon a number offactors, including the intended mode of administration, and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration needed to ameliorate the disease being treatedmay be empirically determined.

Compositions according to the present invention are optionally providedfor administration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, dry powders for inhalers, granules,sterile parenteral solutions or suspensions, and oral solutions orsuspensions, and oil-water emulsions containing suitable quantities ofthe compounds, particularly the pharmaceutically acceptable salts,preferably the sodium salts, thereof. The pharmaceuticallytherapeutically active compounds and derivatives thereof are typicallyformulated and administered in unit-dosage forms or multiple-dosageforms. Unit-dose forms, as used herein, refers to physically discreteunits suitable for human and animal subjects and packaged individuallyas is known in the art. Each unit-dose contains a predetermined quantityof the therapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes individually packaged tablet or capsule. Unit-doseforms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pint or gallons. Hence, multipledose form is a multiple of unit-doses that are not segregated inpackaging.

In addition to one or more compounds according to the present invention,the composition may comprise: a diluent such as lactose, sucrose,dicalcium phosphate, or carboxymethylcellulose; a lubricant, such asmagnesium stearate, calcium stearate and talc; and a binder such asstarch, natural gums, such as gum acaciagelatin, glucose, molasses,polvinylpyrrolidine, celluloses and derivatives thereof, povidone,crospovidones and other such binders known to those of skill in the art.Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, or otherwise mixing an activecompound as defined above and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, glycols, ethanol, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of auxiliary substances suchas wetting agents, emulsifying agents, or solubilizing agents, pHbuffering agents and the like, for example, acetate, sodium citrate,cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodiumacetate, triethanolamine oleate, and other such agents. Actual methodsof preparing such dosage forms are known in the art, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975. The composition or formulation to be administered will,in any event, contain a sufficient quantity of an activator of thepresent invention to increase glucokinase activity in vivo, therebytreating the disease state of the subject.

Dosage forms or compositions may optionally comprise one or morecompounds according to the present invention in the range of 0.005% to100% (weight/weight) with the balance comprising additional substancessuch as those described herein. For oral administration, apharmaceutically acceptable composition may optionally comprise any oneor more commonly employed excipients, such as, for examplepharmaceutical grades of mannitol, lactose, starch, magnesium stearate,talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose,magnesium carbonate, sodium saccharin, talcum. Such compositions includesolutions, suspensions, tablets, capsules, powders, dry powders forinhalers and sustained release formulations, such as, but not limitedto, implants and microencapsulated delivery systems, and biodegradable,biocompatible polymers, such as collagen, ethylene vinyl acetate,polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid andothers. Methods for preparing these formulations are known to thoseskilled in the art. The compositions may optionally contain 0.01%-100%(weight/weight) of one or more glucokinase activators, optionally0.1-95%, and optionally 1-95%.

Salts, preferably sodium salts, of the activators may be prepared withcarriers that protect the compound against rapid elimination from thebody, such as time release formulations or coatings. The formulationsmay further include other active compounds to obtain desiredcombinations of properties.

Formulations for Oral Administration

Oral pharmaceutical dosage forms may be as a solid, gel or liquid.Examples of solid dosage forms include, but are not limited to tablets,capsules, granules, and bulk powders. More specific examples of oraltablets include compressed, chewable lozenges and tablets that may beenteric-coated, sugar-coated or film-coated. Examples of capsulesinclude hard or soft gelatin capsules. Granules and powders may beprovided in non-effervescent or effervescent forms. Each may be combinedwith other ingredients known to those skilled in the art.

In certain embodiments, compounds according to the present invention areprovided as solid dosage forms, preferably capsules or tablets. Thetablets, pills, capsules, troches and the like may optionally containone or more of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders that may be used include, but are not limited to,microcrystalline cellulose, gum tragacanth, glucose solution, acaciamucilage, gelatin solution, sucrose and starch paste.

Examples of lubricants that may be used include, but are not limited to,talc, starch, magnesium or calcium stearate, lycopodium and stearicacid.

Examples of diluents that may be used include, but are not limited to,lactose, sucrose, starch, kaolin, salt, mannitol and dicalciumphosphate.

Examples of glidants that may be used include, but are not limited to,colloidal silicon dioxide.

Examples of disintegrating agents that may be used include, but are notlimited to, crosscarmellose sodium, sodium starch glycolate, alginicacid, corn starch, potato starch, bentonite, methylcellulose, agar andcarboxymethylcellulose.

Examples of coloring agents that may be used include, but are notlimited to, any of the approved certified water-soluble FD and C dyes,mixtures thereof; and water insoluble FD and C dyes suspended on aluminahydrate.

Examples of sweetening agents that may be used include, but are notlimited to, sucrose, lactose, mannitol and artificial sweetening agentssuch as sodium cyclamate and saccharin, and any number of spray-driedflavors.

Examples of flavoring agents that may be used include, but are notlimited to, natural flavors extracted from plants such as fruits andsynthetic blends of compounds that produce a pleasant sensation, suchas, but not limited to peppermint and methyl salicylate.

Examples of wetting agents that may be used include, but are not limitedto, propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate and polyoxyethylene lauryl ether.

Examples of anti-emetic coatings that may be used include, but are notlimited to, fatty acids, fats, waxes, shellac, ammoniated shellac andcellulose acetate phthalates.

Examples of film coatings that may be used include, but are not limitedto, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the salt of the compound mayoptionally be provided in a composition that protects it from the acidicenvironment of the stomach. For example, the composition can beformulated in an enteric coating that maintains its integrity in thestomach and releases the active compound in the intestine. Thecomposition may also be formulated in combination with an antacid orother such ingredient.

When the dosage unit form is a capsule, it may optionally additionallycomprise a liquid carrier such as a fatty oil. In addition, dosage unitforms may optionally additionally comprise various other materials thatmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents.

Compounds according to the present invention may also be administered asa component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may optionally comprise, in addition to theactive compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors.

The compounds of the present invention may also be mixed with otheractive materials that do not impair the desired action, or withmaterials that supplement the desired action, such as antacids, H2blockers, and diuretics. For example, if a compound is used for treatingasthma or hypertension, it may be used with other bronchodilators andantihypertensive agents, respectively.

Examples of pharmaceutically acceptable carriers that may be included intablets comprising compounds of the present invention include, but arenot limited to binders, lubricants, diluents, disintegrating agents,coloring agents, flavoring agents, and wetting agents. Enteric-coatedtablets, because of the enteric-coating, resist the action of stomachacid and dissolve or disintegrate in the neutral or alkaline intestines.Sugar-coated tablets may be compressed tablets to which different layersof pharmaceutically acceptable substances are applied. Film-coatedtablets may be compressed tablets that have been coated with polymers orother suitable coating. Multiple compressed tablets may be compressedtablets made by more than one compression cycle utilizing thepharmaceutically acceptable substances previously mentioned. Coloringagents may also be used in tablets. Flavoring and sweetening agents maybe used in tablets, and are especially useful in the formation ofchewable tablets and lozenges.

Examples of liquid oral dosage forms that may be used include, but arenot limited to, aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules andeffervescent preparations reconstituted from effervescent granules.

Examples of aqueous solutions that may be used include, but are notlimited to, elixirs and syrups. As used herein, elixirs refer to clear,sweetened, hydroalcoholic preparations. Examples of pharmaceuticallyacceptable carriers that may be used in elixirs include, but are notlimited to solvents. Particular examples of solvents that may be usedinclude glycerin, sorbitol, ethyl alcohol and syrup. As used herein,syrups refer to concentrated aqueous solutions of a sugar, for example,sucrose. Syrups may optionally further comprise a preservative.

Emulsions refer to two-phase systems in which one liquid is dispersed inthe form of small globules throughout another liquid. Emulsions mayoptionally be oil-in-water or water-in-oil emulsions. Examples ofpharmaceutically acceptable carriers that may be used in emulsionsinclude, but are not limited to non-aqueous liquids, emulsifying agentsand preservatives.

Examples of pharmaceutically acceptable substances that may be used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents.

Examples of pharmaceutically acceptable substances that may be used ineffervescent granules, to be reconstituted into a liquid oral dosageform, include organic acids and a source of carbon dioxide.

Coloring and flavoring agents may optionally be used in all of the abovedosage forms.

Particular examples of preservatives that may be used include glycerin,methyl and propylparaben, benzoic add, sodium benzoate and alcohol.

Particular examples of non-aqueous liquids that may be used in emulsionsinclude mineral oil and cottonseed oil.

Particular examples of emulsifying agents that may be used includegelatin, acacia, tragacanth, bentonite, and surfactants such aspolyoxyethylene sorbitan monooleate.

Particular examples of suspending agents that may be used include sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluentsinclude lactose and sucrose. Sweetening agents include sucrose, syrups,glycerin and artificial sweetening agents such as sodium cyclamate andsaccharin.

Particular examples of wetting agents that may be used include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurateand polyoxyethylene lauryl ether.

Particular examples of organic acids that may be used include citric andtartaric acid.

Sources of carbon dioxide that may be used in effervescent compositionsinclude sodium bicarbonate and sodium carbonate. Coloring agents includeany of the approved certified water soluble FD and C dyes, and mixturesthereof.

Particular examples of flavoring agents that may be used include naturalflavors extracted from plants such fruits, and synthetic blends ofcompounds that produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603.

Injectables, Solutions, and Emulsions

The present invention is also directed to compositions designed toadminister the compounds of the present invention by parenteraladministration, generally characterized by subcutaneous, intramuscularor intravenous injection. Injectables may be prepared in anyconventional form, for example as liquid solutions or suspensions, solidforms suitable for solution or suspension in liquid prior to injection,or as emulsions.

Examples of excipients that may be used in conjunction with injectablesaccording to the present invention include, but are not limited towater, saline, dextrose, glycerol or ethanol. The injectablecompositions may also optionally comprise minor amounts of non-toxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents, stabilizers, solubility enhancers, and other such agents, suchas for example, sodium acetate, sorbitan monolaurate, triethanolamineoleate and cyclodextrins. Implantation of a slow-release orsustained-release system, such that a constant level of dosage ismaintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplatedherein. The percentage of active compound contained in such parenteralcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject.

Parenteral administration of the formulations includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as the lyophilized powders describedherein, ready to be combined with a solvent just prior to use, includinghypodermic tablets, sterile suspensions ready for injection, sterile dryinsoluble products ready to be combined with a vehicle just prior to useand sterile emulsions. The solutions may be either aqueous ornonaqueous.

When administered intravenously, examples of suitable carriers include,but are not limited to physiological saline or phosphate buffered saline(PBS), and solutions containing thickening and solubilizing agents, suchas glucose, polyethylene glycol, and polypropylene glycol and mixturesthereof.

Examples of pharmaceutically acceptable carriers that may optionally beused in parenteral preparations include, but are not limited to aqueousvehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, local anesthetics, suspending and dispersingagents, emulsifying agents, sequestering or chelating agents and otherpharmaceutically acceptable substances.

Examples of aqueous vehicles that may optionally be used include SodiumChloride Injection, Ringers Injection, Isotonic Dextrose Injection,Sterile Water Injection, Dextrose and Lactated Ringers Injection.

Examples of nonaqueous parenteral vehicles that may optionally be usedinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil.

Antimicrobial agents in bacteriostatic or fungistatic concentrations maybe added to parenteral preparations, particularly when the preparationsare packaged in multiple-dose containers and thus designed to be storedand multiple aliquots to be removed. Examples of antimicrobial agentsthat may be used include phenols or cresols, mercurials, benzyl alcohol,chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters,thimerosal, benzalkonium chloride and benzethonium chloride.

Examples of isotonic agents that may be used include sodium chloride anddextrose. Examples of buffers that may be used include phosphate andcitrate. Examples of antioxidants that may be used include sodiumbisulfate. Examples of local anesthetics that may be used includeprocaine hydrochloride. Examples of suspending and dispersing agentsthat may be used include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Examples of emulsifying agentsthat may be used include Polysorbate 80 (TWEEN 80). A sequestering orchelating agent of metal ions includes EDTA.

Pharmaceutical carriers may also optionally include ethyl alcohol,polyethylene glycol and propylene glycol for water miscible vehicles andsodium hydroxide, hydrochloric acid, citric acid or lactic acid for pHadjustment.

The concentration of an activator in the parenteral formulation may beadjusted so that an injection administers a pharmaceutically effectiveamount sufficient to produce the desired pharmacological effect. Theexact concentration of an activator and/or dosage to be used willultimately depend on the age, weight and condition of the patient oranimal as is known in the art.

Unit-dose parenteral preparations may be packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration should be sterile, as is know and practiced in the art.

Injectables may be designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the glucokinase activator to the treatedtissue(s). The activator may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment willbe a function of the location of where the composition is parenterallyadministered, the carrier and other variables that may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test data. It is to be noted that concentrations anddosage values may also vary with the age of the individual treated. Itis to be further understood that for any particular subject, specificdosage regimens may need to be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the formulations.Hence, the concentration ranges set forth herein are intended to beexemplary and are not intended to limit the scope or practice of theclaimed formulations.

The glucokinase activator may optionally be suspended in micronized orother suitable form or may be derivatized to produce a more solubleactive product or to produce a prodrug. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease state and may be empiricallydetermined.

Lyophilized Powders

The compounds of the present invention may also be prepared aslyophilized powders, which can be reconstituted for administration assolutions, emulsions and other mixtures. The lyophilized powders mayalso be formulated as solids or gels.

Sterile, lyophilized powder may be prepared by dissolving the compoundin a sodium phosphate buffer solution containing dextrose or othersuitable excipient. Subsequent sterile filtration of the solutionfollowed by lyophilization under standard conditions known to those ofskill in the art provides the desired formulation. Briefly, thelyophilized powder may optionally be prepared by dissolving dextrose,sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose orother suitable agent, about 1-20%, preferably about 5 to 15%, in asuitable buffer, such as citrate, sodium or potassium phosphate or othersuch buffer known to those of skill in the art at, typically, aboutneutral pH. Then, a glucokinase activator is added to the resultingmixture, preferably above room temperature, more preferably at about30-35° C., and stirred until it dissolves. The resulting mixture isdiluted by adding more buffer to a desired concentration. The resultingmixture is sterile filtered or treated to remove particulates and toinsure sterility, and apportioned into vials for lyophilization. Eachvial may contain a single dosage or multiple dosages of the activator.

Topical Administration

The compounds of the present invention may also be administered astopical mixtures. Topical mixtures may be used for local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The glucokinase activators may be formulated as aerosols for topicalapplication, such as by inhalation (see, U.S. Pat. Nos. 4,044,126,4,414,209, and 4,364,923, which describe aerosols for delivery of asteroid useful for treatment of inflammatory diseases, particularlyasthma). These formulations for administration to the respiratory tractcan be in the form of an aerosol or solution for a nebulizer, or as amicrofine powder for insufflation, alone or in combination with an inertcarrier such as lactose. In such a case, the particles of theformulation will typically have diameters of less than 50 microns,preferably less than 10 microns.

The activators may also be formulated for local or topical application,such as for topical application to the skin and mucous membranes, suchas in the eye, in the form of gels, creams, and lotions and forapplication to the eye or for intracisternal or intraspinal application.Topical administration is contemplated for transdermal delivery and alsofor administration to the eyes or mucosa, or for inhalation therapies.Nasal solutions of the glucokinase activator alone or in combinationwith other pharmaceutically acceptable excipients can also beadministered.

Formulations for Other Routes of Administration

Depending upon the disease state being treated, other routes ofadministration, such as topical application, transdermal patches, andrectal administration, may also be used. For example, pharmaceuticaldosage forms for rectal administration are rectal suppositories,capsules and tablets for systemic effect. Rectal suppositories are usedherein mean solid bodies for insertion into the rectum that melt orsoften at body temperature releasing one or more pharmacologically ortherapeutically active ingredients. Pharmaceutically acceptablesubstances utilized in rectal suppositories are bases or vehicles andagents to raise the melting point. Examples of bases include cocoabutter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethyleneglycol) and appropriate mixtures of mono-, di- and triglycerides offatty acids. Combinations of the various bases may be used. Agents toraise the melting point of suppositories include spermaceti and wax.Rectal suppositories may be prepared either by the compressed method orby molding. The typical weight of a rectal suppository is about 2 to 3gm. Tablets and capsules for rectal administration may be manufacturedusing the same pharmaceutically acceptable substance and by the samemethods as for formulations for oral administration.

Examples of Formulations

The following are particular examples of oral, intravenous and tabletformulations that may optionally be used with compounds of the presentinvention. It is noted that these formulations may be varied dependingon the particular compound being used and the indication for which theformulation is going to be used.

Oral Formulation

Compound of the Present Invention 10-100 mg Citric Acid Monohydrate   105 mg Sodium Hydroxide     18 mg Flavoring Water q.s. to 100 mL

Intravenous Formulation

Compound of the Present Invention 0.1-10 mg  Dextrose Monohydrate q.s.to make isotonic Citric Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18mg Water for Injection q.s. to 1.0 mL

Tablet Formulation

Compound of the Present Invention  1% Microcrystalline Cellulose 73%Stearic Acid 25% Colloidal Silica  1%.

Kits Comprising Glucokinase Activators

The invention is also directed to kits and other articles of manufacturefor treating diseases associated with glucokinase. It is noted thatdiseases are intended to cover all conditions for which increasingglucokinase activity (e.g., upregulation of glucokinase) ameliorates thepathology and/or symptomology of the condition.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one activator of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one activator of the presentinvention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

It is noted that the packaging material used in kits and articles ofmanufacture according to the present invention may form a plurality ofdivided containers such as a divided bottle or a divided foil packet.The container can be in any conventional shape or form as known in theart which is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.The container that is employed will depend on the exact dosage forminvolved, for example a conventional cardboard box would not generallybe used to hold a liquid suspension. It is feasible that more than onecontainer can be used together in a single package to market a singledosage form. For example, tablets may be contained in a bottle that isin turn contained within a box. Typically the kit includes directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral, topical, transdermaland parenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

One particular example of a kit according to the present invention is aso-called blister pack. Blister packs are well known in the packagingindustry and are being widely used for the packaging of pharmaceuticalunit dosage forms (tablets, capsules, and the like). Blister packsgenerally consist of a sheet of relatively stiff material covered with afoil of a preferably transparent plastic material. During the packagingprocess recesses are formed in the plastic foil. The recesses have thesize and shape of individual tablets or capsules to be packed or mayhave the size and shape to accommodate multiple tablets and/or capsulesto be packed. Next, the tablets or capsules are placed in the recessesaccordingly and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are individually sealed or collectively sealed, as desired, inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

Another specific embodiment of a kit is a dispenser designed to dispensethe daily doses one at a time in the order of their intended use.Preferably, the dispenser is equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter that indicates the number of dailydoses that has been dispensed. Another example of such a memory-aid is abattery-powered micro-chip memory coupled with a liquid crystal readout,or audible reminder signal which, for example, reads out the date thatthe last daily dose has been taken and/or reminds one when the next doseis to be taken.

Dosage, Host and Safety

The compounds of the present invention are stable and can be usedsafely. In particular, the compounds of the present invention are usefulas glucokinase activators for a variety of subjects (e.g., humans,non-human mammals and non-mammals). The optimal dose may vary dependingupon such conditions as, for example, the type of subject, the bodyweight of the subject, the route of administration, and specificproperties of the particular compound being used. In general, the dailydose for oral administration to an adult (body weight of about 60 kg) isabout 1 to 1000 mg, about 3 to 300 mg, or about 10 to 200 mg. It will beappreciated that the daily dose can be given in a single administrationor in multiple (e.g., 2 or 3) portions a day.

Combination Therapies

A wide variety of therapeutic agents may have a therapeutic additive orsynergistic effect with GK activators according to the presentinvention. In particular, the present invention also relates to the useof the GK activators of the present invention in combination with one ormore other antidiabetic compounds. Examples of such other antidiabeticcompounds include, but are not limited to S9 proteases, like dipeptidylpeptidase IV (DPP-IV) inhibitors; insulin signaling pathway modulators,like protein tyrosine phosphatase (PTPase) inhibitors, andglutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitors;compounds influencing a dysregulated hepatic glucose production, likeglucose-6-phosphatase (G6Pase) inhibitors, fructose-1,6-bisphosphatase(F-1,6-BPase) inhibitors, glycogen phosphorylase (GP) inhibitors,glucagon receptor antagonists and phosphoenolpyruvate carboxykinase(PEPCK) inhibitors; pyruvate dehydrogenase kinase (PDHK) inhibitors;insulin sensitivity enhancers (insulin sensitizers); insulin secretionenhancers (insulin secretagogues); alpha-glucosidase inhibitors;inhibitors of gastric emptying; other glucokinase (GK) activators; GLP-1receptor agonists; UCP modulators; RXR modulators; GSK-3 inhibitors;PPAR modulators; metformin; insulin; and 2-adrenergic antagonists.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally be DPP-IVinhibitors selected from the group consisting of Alogliptin (Nesina;Takeda Pharmaceutical Company Limited), Sitagliptin (Januvia; Merck),Saxagliptin (Onglyza; Bristol Myers Squibb), and Vildagliptin (Galvus;Novartis). In addition, the one or more antidiabetic compoundsadministered in combination with the GK activators of the presentinvention may also optionally be DPP-IV inhibitors combined withmetformin such as, for example, Alogliptin plus metformin (TakedaPharmaceutical Company Limited), Sitagliptin plus metformin (Janumet;Merck), Saxagliptin plus metformin (Bristol Myers Squibb), andVildagliptin plus metformin (Eucreas; Novartis).

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally beselected from the group consisting of protein tyrosine phosphataseinhibitors, glutamine-fructose-6-phosphate amidotransferase inhibitors,glucose-6-phosphatase inhibitors, fructose-1,6-bisphosphataseinhibitors, glycogen phosphorylase inhibitors, glucagon receptorantagonists, phosphoenolpyruvate carboxykinase inhibitors, pyruvatedehydrogenase kinase inhibitors, alpha-glucosidase inhibitors,inhibitors of gastric emptying, glucokinase activators, GLP-1 receptoragonists, GLP-2 receptor agonists, UCP modulators, RXR modulators, GSK-3inhibitors, PPAR modulators, metformin, insulin, and α₂-adrenergicantagonists.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally beselected from the group consisting of GSK-3 inhibitors, retinoid Xreceptor agonists, Beta-3 AR agonists, UCP modulators, antidiabeticthiazolidinediones, non-glitazone type PPAR gamma agonists, dual PPARgamma/PPAR alpha agonists, antidiabetic vanadium containing compoundsand biguanides.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally bethiazolidinediones selected from the group consisting of(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione,5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thiazolidine-2,4-dione,5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl]-thiazolidine-2,4-dione,5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione,5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-dione,5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione, bis{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane,5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolidine-2,4-dione,5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione,5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-dione,5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione,5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione,5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione,5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione,5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl)-thiazolidine-2,4-dione,5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2,4-dione,5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione and5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide,including any pharmaceutically acceptable salts thereof.

In one variation, the one or more antidiabetic compounds administered incombination with the GK activators of the present invention includesmetformin. In one particular variation, the metformin in thiscombination comprises one or more pharmaceutically acceptable saltsthereof. In another particular variation, the metformin in thiscombination comprises a metformin HCl salt. In still another particularvariation, the metformin in this combination is administered in a dailydose of between 125 and 2550 mg. In yet another variation, the metforminin this combination is administered in a daily dose of between 250 and2550 mg.

In another variation, the one or more antidiabetic compoundsadministered in combination with the GK activators of the presentinvention includes one or more sulphonyl urea derivatives.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally beselected from the group consisting of glisoxepid, glyburide,glibenclamide, acetohexamide, chloropropamide, glibornuride,tolbutamide, tolazamide, glipizide, carbutamide, gliquidone,glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide,including any pharmaceutically acceptable salts thereof. In onevariation, the one or more antidiabetic compounds administered incombination with the GK activators of the present invention includesglimepiride.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally beselected from the group consisting of incretin hormones or mimicsthereof, beta-cell imidazoline receptor antagonists, and short-actinginsulin secretagogues.

In another variation, the one or more antidiabetic compoundsadministered in combination with the GK activators of the presentinvention includes insulin.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally be one ormore GLP-1 agonists including, for example, extendatide.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally be one ormore GLP-2 agonists including, for example, human recombinant GLP-2.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally be one ormore antidiabetic D-phenylalanine derivatives.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally beselected from the group consisting of repaglinide, mitiglinide, andnateglinide, including any pharmaceutically acceptable salts thereof. Inone variation, the one or more antidiabetic compounds administered incombination with the GK activators of the present invention includesmitiglinide calcium salt hydrate.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally be one ormore alpha-Glucosidase inhibitors.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally beselected from the group consisting of acarbose, voglibose and miglitol,including any pharmaceutically acceptable salts thereof. In onevariation, the one or more antidiabetic compounds administered incombination with the GK activators of the present invention includesvoglibose. In another variation, the voglibose in this combination isadministered in a daily dose of between 0.1 and 1 mg.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally berosiglitazone, including any pharmaceutically acceptable salts thereof.In one variation, the rosiglitazone in this combination comprises arosiglitazone maleate salt.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally betesaglitazar, muraglitazar or naveglitazar, including anypharmaceutically acceptable salts thereof.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally bepioglitazone, including any pharmaceutically acceptable salts thereof.In one variation, the pioglitazone in this combination comprises apioglitazone HCl salt. In another variation, the pioglitazone in thiscombination is administered in a daily dose of between 7.5 and 60 mg. Instill another variation, the pioglitazone in this combination isadministered in a daily dose of between 15 and 45 mg.

The one or more antidiabetic compounds administered in combination withthe GK activators of the present invention may also optionally comprisemetformin and pioglitazone. In one variation, the pioglitazone in thiscombination comprises one or more pharmaceutically acceptable saltsthereof. In another variation, the pioglitazone in this combinationcomprises a pioglitazone HCl salt. In still another variation, thepioglitazone in this combination is administered in a daily dose ofbetween 7.5 and 60 mg. In yet another variation, the pioglitazone inthis combination is administered in a daily dose of between 15 and 45mg. In another variation of each of the above variations, the metforminin this combination comprises one or more pharmaceutically acceptablesalts thereof. In one particular variation, the metformin in thiscombination comprises a metformin HCl salt. In another particularvariation, the metformin in this combination is administered in a dailydose of between 125 and 2550 mg. In still another variation, themetformin in this combination is administered in a daily dose of between250 and 2550 mg.

In the case of combination therapy with compounds of the presentinvention, the other antidiabetic compound may be administered (e.g.,route and dosage form) in a manner known per se for such compound.Compounds of the present invention and the other antidiabetic compoundmay be administered sequentially (i.e., at separate times) or at thesame time, either one after the other separately in two separate doseforms or in one combined, single dose form. In one particularembodiment, the other antidiabetic compound is administered withcompounds of the present invention as a single, combined dosage form.The dose of the antidiabetic compound may be selected from the rangeknown to be clinically employed for such compound. Any of thetherapeutic compounds of diabetic complications, antihyperlipemiccompounds or antiobestic compounds can be used in combination withcompounds of the present invention in the same manner as the aboveantidiabetic compounds.

Examples Preparation of Glucokinase Activators

Various methods may be developed for synthesizing compounds according tothe present invention. Representative methods for synthesizing thesecompounds are provided in the Examples. It is noted, however, that thecompounds of the present invention may also be synthesized by othersynthetic routes that others may devise.

It will be readily recognized that certain compounds according to thepresent invention have atoms with linkages to other atoms that confer aparticular stereochemistry to the compound (e.g., chiral centers). It isrecognized that synthesis of compounds according to the presentinvention may result in the creation of mixtures of differentstereoisomers (i.e., enantiomers and diastereomers). Unless a particularstereochemistry is specified, recitation of a compound is intended toencompass all of the different possible stereoisomers.

Various methods for separating mixtures of different stereoisomers areknown in the art. For example, a racemic mixture of a compound may bereacted with an optically active resolving agent to form a pair ofdiastereoisomeric compounds. The diastereomers may then be separated inorder to recover the optically pure enantiomers. Dissociable complexesmay also be used to resolve enantiomers (e.g., crystallinediastereoisomeric salts). Diastereomers typically have sufficientlydistinct physical properties (e.g., melting points, boiling points,solubilities, reactivity, etc.) and can be readily separated by takingadvantage of these dissimilarities. For example, diastereomers cantypically be separated by chromatography or by separation/resolutiontechniques based upon differences in solubility. A more detaileddescription of techniques that can be used to resolve stereoisomers ofcompounds from their racemic mixture can be found in Jean Jacques AndreCollet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, JohnWiley & Sons, Inc. (1981).

Compounds according to the present invention can also be prepared as apharmaceutically acceptable acid addition salt by reacting the free baseform of the compound with a pharmaceutically acceptable inorganic ororganic acid. Alternatively, a pharmaceutically acceptable base additionsalt of a compound can be prepared by reacting the free acid form of thecompound with a pharmaceutically acceptable inorganic or organic base.Inorganic and organic acids and bases suitable for the preparation ofthe pharmaceutically acceptable salts of compounds are set forth in thedefinitions section of this Application. Alternatively, the salt formsof the compounds can be prepared using salts of the starting materialsor intermediates.

The free acid or free base forms of the compounds can be prepared fromthe corresponding base addition salt or acid addition salt form. Forexample, a compound in an acid addition salt form can be converted tothe corresponding free base by treating with a suitable base (e.g.,ammonium hydroxide solution, sodium hydroxide, and the like). A compoundin a base addition salt form can be converted to the corresponding freeacid by treating with a suitable acid (e.g., hydrochloric acid, etc).

The N-oxides of compounds according to the present invention can beprepared by methods known to those of ordinary skill in the art. Forexample, N-oxides can be prepared by treating an unoxidized form of thecompound with an oxidizing agent (e.g., trifluoroperacetic acid,permaleic acid, perbenzoic acid, peracetic acid,meta-chloroperoxybenzoic acid, or the like) in a suitable inert organicsolvent (e.g., a halogenated hydrocarbon such as dichloromethane) atapproximately 0° C. Alternatively, the N-oxides of the compounds can beprepared from the N-oxide of an appropriate starting material.

Compounds in an unoxidized form can be prepared from N-oxides ofcompounds by treating with a reducing agent (e.g., sulfur, sulfurdioxide, triphenyl phosphine, lithium borohydride, sodium borohydride,phosphorus trichloride, tribromide, or the like) in an suitable inertorganic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or thelike) at 0 to 80° C.

Prodrug derivatives of the compounds can be prepared by methods known tothose of ordinary skill in the art (e.g., for further details seeSaulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p. 1985). For example, appropriate prodrugs can be prepared byreacting a non-derivatized compound with a suitable carbamylating agent(e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, orthe like).

Protected derivatives of the compounds can be made by methods known tothose of ordinary skill in the art. A detailed description of thetechniques applicable to the creation of protecting groups and theirremoval can be found in T.W. Greene, Protecting Groups in OrganicSynthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds according to the present invention may be convenientlyprepared, or formed during the process of the invention, as solvates(e.g., hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds according to the present invention can also be prepared astheir individual stereoisomers by reacting a racemic mixture of thecompound with an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomer. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of compounds,dissociable complexes are preferred (e.g., crystalline diastereoisomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubilities, reactivity, etc.) and can bereadily separated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

μL (microliters) Ac (acetyl) atm (atmosphere) ATP (AdenosineTriphophatase) BOC (tert-butyloxycarbonyl) BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride) BSA (Bovine Serum Albumin) CBZ(benzyloxycarbonyl) CDI (1,1-carbonyldiimidazole) DCC(dicyclohexylcarbodiimide) DCE (dichloroethane) DCM (dichloromethane)DMAP (4-dimethylaminopyridine) DME (1,2-dimethoxyethane) DMF(N,N-dimethylformamide) DMPU (N,N′-dimethylpropyleneurea) DMSO(dimethylsulfoxide) EDCI (ethylcarbodiimide hydrochloride) EDTA(Ethylenediaminetetraacetic Et (ethyl) acid) Et₂O (diethyl ether) EtOAc(ethyl acetate) FMOC (9-fluorenylmethoxy- g (grams) carbonyl) h (hours)HOAc or AcOH (acetic acid) HOBT (1-hydroxybenzotriazole) HOSu(N-hydroxysuccinimide) HPLC (high pressure liquid Hz (Hertz)chromatography) i.v. (intravenous) IBCF (isobutyl chloroformate) i-PrOH(isopropanol) L (liters) M (molar) mCPBA (meta-chloroperbenzoic acid) Me(methyl) MeOH (methanol) mg (milligrams) MHz (megahertz) min (minutes)mL (milliliters) mM (millimolar) mmol (millimoles) mol (moles) MOPS(Morpholinepropanesulfonic acid) mp (melting point) NaOAc (sodiumacetate) OMe (methoxy) psi (pounds per square inch) RP (reverse phase)RT (ambient temperature) SPA (Scintillation Proximity TBAF(tetra-n-butylammonium Assay) fluoride) TBS (t-butyldimethylsilyl) tBu(tert-butyl) TEA (triethylamine) TFA (trifluoroacetic acid) TFAA(trifluoroacetic anhydride) THF (tetrahydrofuran) TIPS(triisopropylsilyl) TLC (thin layer chromatography) TMS (trimethylsilyl)TMSE (2-(trimethylsilyl)ethyl) Tr (retention time)

All references to ether or Et₂O are to diethyl ether; and brine refersto a saturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at RT unless otherwise noted.

¹H NMR spectra were recorded on a Bruker Avance 400. Chemical shifts areexpressed in parts per million (ppm). Coupling constants are in units ofHertz (Hz). Splitting patterns describe apparent multiplicities and aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), br (broad).

Low-resolution mass spectra (MS) and compound purity data were acquiredon a Waters ZQ LC/MS single quadrupole system equipped with electrosprayionization (ESI) source, UV detector (220 and 254 nm), and evaporativelight scattering detector (ELSD). Thin-layer chromatography wasperformed on 0.25 mm E. Merck silica gel plates (60F-254), visualizedwith UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin orp-anisaldehyde solution. Flash column chromatography was performed onsilica gel (230-400 mesh, Merck).

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as the AldrichChemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma(St. Louis, Mo.), or may be prepared by methods well known to a personof ordinary skill in the art, following procedures described in suchstandard references as Fieser and Fieser's Reagents for OrganicSynthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd'sChemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier SciencePublishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons,New York, N.Y., 1991; March J.: Advanced Organic Chemistry, 4th ed.,John Wiley and Sons, New York, N.Y.; and Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

The entire disclosures of all documents cited throughout thisapplication are incorporated herein by reference.

Synthetic Schemes for Compounds of the Present Invention

Compounds according to the present invention may be synthesizedaccording to the reaction schemes shown below. Other reaction schemescould be readily devised by those skilled in the art. It should also beappreciated that a variety of different solvents, temperatures and otherreaction conditions can be varied to optimize the yields of thereactions.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T.W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1991.

General synthetic routes for producing compounds of the presentinvention are shown below.

Referring to Scheme A, a halo-pyrazole (A1, wherein G₁ is a leavinggroup (e.g., halo such as bromo)) and a disulfide are treated with NiBrand Zn in the presence of 2,2′-bipyridine to give intermediates A2.Subsequent treatment of A2 with base and reagent A3 (wherein G₂ is aleaving group (e.g., halo such as bromo)) affords intermediates A4.Oxidation of the sulfur functionality of A4 with Oxone® gives analogs A5which are then treated with various amine containing molecules to affordamides A6.

Referring to Scheme B, a halo-pyrazole (B1, wherein G₁ is a leavinggroup (e.g., halo such as bromo)) is treated with base and reagent B2(wherein G₂ is a leaving group (e.g., halo such as bromo)) to affordintermediates B3. Subsequent treatment of this material with variousmercaptans in the presence of tris(dibenzylacetone)dipalladium and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene affords B5. Oxidation ofthe sulfur functionality of B5 gives analogs B6 which are then treatedwith various amine containing molecules to give amides B7.

Referring to Scheme C, ester C1 which can be generated, for example,according to Scheme B is saponified to the acid C2 and coupled with anamino heterocycle C3 to obtain the intermediate C4. This intermediate onsaponification gives the target compound C5.

Referring to Scheme D, intermediate D3 can be obtained by treatment of asubstituted pyrazole-3-carbonyl chloride (D1, wherein G₃ is a leavinggroup (e.g., halo such as chloro)) with an amine D2 in the presence of abase. Alkylation followed by coupling with the amino heterocycle D6 canbe done using an analogous procedure as in Scheme A to obtain the targetcompound D7.

Referring to Scheme E, a nitro pyrazole E1 is treated with a base andreagent E2 (wherein G₂ is a leaving group (e.g., halo such as bromo)) toafford intermediate E3. Reduction of the nitro group followed bytreatment with an electrophile E5 (wherein G₆ is a leaving group (e.g.,halo such as chloro)) in the presence of a base gives the intermediateE6. Coupling with an amine gives the target compound E7.

Referring to Scheme F, a substituted indazole (F1, wherein G₄ is aleaving group (e.g., halo such as bromo)) is treated with reagent F2(wherein G₂ is a leaving group (e.g., halo such as bromo)) in thepresence of a base to obtain a mixture of N-1 and N-2 alkylated productsF3 which can be separated by flash column chromatography. Introductionof the sulfone group can be achieved by coupling in the presence of Pdor Cu to obtain intermediate F5, which is then treated with an amine toobtain the desired target F6.

Referring to Scheme G, a substituted indazole (G1, wherein G₄ is aleaving group (e.g., halo such as bromo)) is treated with an alkylhalide (G2, wherein G₂ is a leaving group (e.g., halo such as bromo) andG₅ is a protecting group (e.g., benzyl)) in the presence of a base toobtain a mixture of N-1 and N-2 alkylated products (G3) which can beseparated by flash column chromatography. Introduction of the sulfonegroup can be achieved by coupling in the presence of Pd or Cu to obtainintermediate G5 which is then treated with an amine to obtain theintermediate (G6). Deprotection of the benzyl group followed byoxidation of the alcohol gives the desired target (G7).

Referring to Scheme H, a substituted pyrazole H1, is treated withreagent A3 (wherein G₂ is a leaving group (e.g., halo such as bromo)) inthe presence of a base to obtain a mixture of alkylated products H2which can be separated by column chromatography. Hydrolysis of the esterto H3, followed by coupling with an amine gives the target compound H4

Referring to Scheme I, ortho lithiation of I1, wherein G₄ is a leavinggroup (e.g., halo such as fluoro), followed by introduction of thealdehyde ortho to the fluoride gives I2. Treatment with hydrazine givesthe hydrazone which cyclizes to an intermediate indazole on heating.Introduction of the sulfone group can be achieved either by displacementwith a sulfinate or by coupling in the presence of Pd or Cu to obtainintermediate I3. The indazole I3 is treated with reagent I4 (wherein G₂is a leaving group (e.g., halo such as bromo)) in the presence of a baseto obtain a mixture of N-1 and N-2 alkylated products I5 and I6, whichcan be separated by flash column chromatography. Treatment of I5 and/orI6 with an amine gives the desired targets I7 and I8, respectively.

Referring to Scheme J, bromination of 3-methyl-4-nitrophenol gives amixture of regioisomers which can be separated by column chromatography.Treatment of J1 with an alkyl halide (J2, wherein G5 is a leaving group(e.g., halo such as bromine)) in the presence of a base gives J3.Reduction of the nitro group yields J4 which can then be treated withisoamyl nitrite in the presence of a base to obtain the substitutedindazole J5. The substituted indazole J5 is treated with reagent A3(wherein G₂ is a leaving group (e.g., halo such as bromo)) in thepresence of a base to obtain a mixture of N-1 and N-2 alkylated productsJ6 and J7, which can be separated by flash column chromatography.Introduction of a sulfone group on J6 and/or J7 can be achieved bycoupling in the presence of Pd or Cu to obtain intermediates J8 and J9,respectively. J8 and/or J9 can then be treated with an amine to obtainJ10 and J11, respectively.

Chiral components can be separated and purified using any of a varietyof techniques known to those skilled in the art. For example, chiralcomponents can be purified using supercritical fluid chromatography(SFC). In one particular variation, chiral analytical SFC/MS analysesare conducted using a Berger analytical SFC system (AutoChem, Newark,Del.) which consists of a Berger SFC dual pump fluid control module witha Berger FCM 1100/1200 supercritical fluid pump and FCM 1200 modifierfluid pump, a Berger TCM 2000 oven, and an Alcott 718 autosampler. Theintegrated system can be controlled by BI-SFC Chemstation softwareversion 3.4. Detection can be accomplished with a Waters ZQ 2000detector operated in positive mode with an ESI interface and a scanrange from 200-800 Da with 0.5 second per scan. Chromatographicseparations can be performed on a ChiralPak AD-H, ChiralPak AS-H,ChiralCel OD-H, or ChiralCel OJ-H column (5μ, 4.6×250 mm; ChiralTechnologies, Inc. West Chester, Pa.) with 10 to 40% methanol as themodifier and with or without ammonium acetate (10 mM). Any of a varietyof flow rates can be utilized including, for example, 1.5 or 3.5 mL/minwith an inlet pressure set at 100 bar. Additionally, a variety of sampleinjection conditions can be used including, for example, sampleinjections of either 5 or 10 μL in methanol at 0.1 mg/mL inconcentration.

In another variation, preparative chiral separations are performed usinga Berger MultiGram II SFC purification system. For example, samples canbe loaded onto a ChiralPak AD column (21×250 mm, 10μ). In particularvariations, the flow rate for separation can be 70 mL/min, the injectionvolume up to 2 mL, and the inlet pressure set at 130 bar. Stackedinjections can be applied to increase the efficiency.

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

Descriptions of the syntheses of particular compounds according to thepresent invention based on the above reaction schemes are set forthherein.

Examples of Glucokinase Activators

The present invention is further exemplified, but not limited by, thefollowing examples that describe the synthesis of particular compoundsaccording to the invention.

Compound 12-(3-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide

3-bromo-1H-pyrazole (1.0 g, 6.8 mmole), NiBr (0.148 g, 0.68 mmole),2,2′-bipyridine (0.106 g, 0.68 mmole), Zinc dust (0.993 g, 13.6 mmole)and 1,2-dicyclopropyldisulfane (0.993 g, 6.8 mmole) were added to asolution of DMF (20 mL) and the mixture was heated under N₂ for 18 h at80° C. The solvent was removed from the crude reaction mixture undervacuum and the orange gum was treated with MeOH. The resulting ppt wasfiltered and discarded. Purification of the filtrate with preparativescale HPLC afforded compound 1A as light brown oil (367 mg). [M+H]calc'd for C₆H₉N₂S, 141.04. found 141.0. ¹H NMR (400 MHz, CHLOROFORM-d)δ ppm 0.73 (q, J=5.05 Hz, 2H) 1.02-1.17 (m, 2H) 2.26 (ddd, J=7.58, 3.66,3.41 Hz, 1H) 6.48 (br. s., 1H) 7.82 (br. s., 1H).

3-(cyclopropylthio)-1H-pyrazole (1A) (0.083 g, 0.6 mmole) was dissolvedin NMP (2 mL) and the solution was chilled to 0° C. NaH (0.060 g, 1.8mmole) was added and when the reaction subsided methyl2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.060 g, 1.8 mmole) wasintroduced, and the reaction was heated at 80° C. for 1 h. The reactionwas cooled and quenched with a small volume of MeOH and the crudemixture was purified using preparative scale HPLC. Compound 1B as wellas a small amount of the carboxylic acid of 1B were collected. Removalof the solvent and treatment of the acid with TMSCH₂N₂ followed bycombination with 1B afforded title compound as oil (81 mg). [M+H] calc'dfor C₁₅H₂₃N₂O₃S (1B ester), 311.14. found 311.0; [M+H] calc'd forC₁₄H₂₁N₂O₃S (1B acid), 297.12. found 297.0.

Compound 1B used directly from the preceding step was treated withOxone® (0.147 g, 0.24 mmole) in a 1:1 solution of THF/H₂O (10 mL). Afteroxidation was judged complete the solvent was removed and the residuewas portioned between EtOAc and H₂O. The organic layer was separated,dried and concentrated to yield crude compound 1C as oil. This materialwas purified using preparative scale HPLC and used directly in the nextstep, [M+H] calc'd for C₁₅H₂₃N₂O₅S, 343.12. found 343.3.

5-Methoxythiazolo[5,4-b]pyridin-2-amine (0.048 g, 0.26 mmole) was addedto a microwave vial followed by DCE (2 mL). The reaction mixture wascooled to 0° C. under a N₂ atmosphere. Trimethyl aluminum (2M inhexanes) (0.13 mL, 0.26 mmole) was added and when the reaction subsidedthe cooling bath was removed, the solution was then stirred at RT for 15min. To this was added a solution of methyl2-(3-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate1C (0.015 g, 0.04 mmole) in DCE (2 mL) and the reaction mixture washeated in a microwave at 110° C. for 1 h. The reaction was then quenchedwith 1N HCl and extracted 2× with DCM. The organic layers were pooled,dried over Na₂SO₄; the solvent was removed and the crude residue waspurified by preparative scale HPLC to afford compound 1 (46 mg). [M+H]calc'd for C₂₁H₂₆N₅O₅S₂, 492.13. found 492.0. ¹H NMR (400 MHz, MeOD) dppm 1.07 (dd, J=7.96, 2.15 Hz, 2H) 1.18-1.42 (m, 6H) 1.52 (d, J=9.35 Hz,1H) 1.74 (d, J=2.02 Hz, 1H) 2.14 (t, J=6.32 Hz, 1H) 2.32 (t, J=10.48 Hz,1H) 2.61-2.80 (m, 1H) 3.29 (m, 1H, under MeOD signal) 3.79-3.98 (m, 5H)5.50 (ddd, J=10.80, 5.68, 5.49 Hz, 1H) 6.81-6.90 (m, 2H) 7.94 (d, J=8.84Hz, 1H) 8.10 (d, J=2.53 Hz, 1H)

Compounds 2 and 3(S)-2-(3-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamideand(R)-2-(3-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide

Compound 1 was subjected to chiral separation on a Berger SFCinstrument. For this particular compound, it was found that usingChiralpak AD-H media eluting with 16% MeOH to afford Compounds 2 and 3was optimal.

Compound 2: [M+H] calc'd for C₂₁H₂₆N₅O₅S₂, 492.13. found 492.0. ¹H NMR(400 MHz, MeOD) δ ppm 1.07 (dd, J=7.96, 2.15 Hz, 2H) 1.18-1.42 (m, 6H)1.52 (d, J=9.35 Hz, 1H) 1.74 (d, J=2.02 Hz, 1H) 2.14 (t, J=6.32 Hz, 1H)2.32 (t, J=10.48 Hz, 1H) 2.61-2.80 (m, 1H) 3.29 (m, 1H, under MeODsignal) 3.79-3.98 (m, 5H) 5.50 (ddd, J=10.80, 5.68, 5.49 Hz, 1H)6.81-6.90 (m, 2H) 7.94 (d, J=8.84 Hz, 1H) 8.10 (d, J=2.53 Hz, 1H)

Compound 3: [M+H] calc'd for C₂₁H₂₆N₅O₅S₂, 492.13. found 492.0. ¹H NMR(400 MHz, MeOD) δ ppm 1.07 (dd, J=7.96, 2.15 Hz, 2H) 1.18-1.42 (m, 6H)1.52 (d, J=9.35 Hz, 1H) 1.74 (d, J=2.02 Hz, 1H) 2.14 (t, J=6.32 Hz, 1H)2.32 (t, J=10.48 Hz, 1H) 2.61-2.80 (m, 1H) 3.29 (m, 1H, under MeODsignal) 3.79-3.98 (m, 5H) 5.50 (ddd, J=10.80, 5.68, 5.49 Hz, 1H)6.81-6.90 (m, 2H) 7.94 (d, J=8.84 Hz, 1H) 8.10 (d, J=2.53 Hz, 1H)

Compound 4N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide

4-bromo-1H-pyrazole (4.0 g, 26.9 mmole) was dissolved in THF (100 mL)and chilled to 0° C. 1.6 M n-BuLi in THF was added and the reactionmixture was stirred for 1 h at RT The reaction was then cooled to 0° C.and 1,2-dicyclopropyldisulfane (3.9 g, 26.9 mmole) was added; thereaction was stirred for 1 h at 0° C. and quenched with sat NH4Cl andextracted with EtOAc. The crude product was obtained as an oil and useddirectly in the next step. [M+H] calc'd for C₆H₉N₂S, 141.04. found141.9.

4-(cyclopropylthio)-1H-pyrazole (4A) (1.0 g, 7.14 mmole) was dissolvedin NMP (5 mL) and the solution was chilled to 0° C. NaH (0.263 g, 7.9mmole) was added and when the reaction subsided methyl2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate (1.1 g, 7.9 mmole) wasintroduced, and the reaction was heated at 80° C. for 1 h. The reactionwas cooled and quenched with a small volume of MeOH and the crudemixture was purified using preparative scale HPLC. Compound 4B as wellas a small amount of the carboxylic acid of 4B were collected. Removalof the solvent and treatment of the acid with TMSCH₂N₂ followed bycombination with 4B afforded title compound as oil (0.68 g). [M+H]calc'd for C₁₅H₂₃N₂O₃S (4B ester), 311.14. found 311.2; [M+H] calc'd forC₁₄H₂₁N₂O₃S (4B acid), 297.12. found 297.1.

Compound 4B (0.68 g, 1.9 mmole) was treated with Oxone® (2.4 g, 3.8mmole) in a 1:1 solution of MeOH/H₂O (20 mL). After oxidation was judgedcomplete the solvent was removed and the residue was portioned betweenEtOAc and H₂O. The organic layer was separated, dried and concentratedto yield crude compound 4C as oil (0.729 g). This material was purifiedusing preparative scale HPLC and used directly in the next step, [M+H]calc'd for C₁₅H₂₃N₂O₅S, 343.12. found 343.0.

5-chlorothiazol-2-amine (0.519 g, 3.03 mmole) was added to a microwavevial followed by DCE (3 mL). The reaction mixture was cooled to 0° C.under a N₂ atmosphere. Trimethyl aluminum (2M in hexanes) (2.6 mmole)was added and when the reaction subsided the cooling bath was removed,the solution was then stirred at RT for 15 min. To this was added asolution of methyl2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate4C (0.173 g, 0.51 mmole) in DCE (2 mL) and the reaction mixture washeated in a microwave at 110° C. for 1 h. The reaction was then quenchedwith 1N HCl and extracted 2× with DCM. The organic layers were pooled,dried over Na₂SO₄ and the solvent was removed. This crude residue waspurified by preparative scale HPLC to afford compound 4 (0.21 g). [M+H]calc'd for C₁₇H2₂ClN₄O₄S₂, 445.07. found 445.2. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.93-1.75 (m, 9H) 2.19 (br. s., 2H) 2.55 (br. s.,1H) 3.31 (br. s., 2H) 3.94 (br. s., 2H) 5.10 (br. s., 1H) 7.32 (s, 1H)8.01 (d, J=9.35 Hz, 2H) 10.35 (bs, 1H)

Compound 5N-(5-chlorothiazol-2-yl)-2-(4-(cyclopentylsulfonyl)-1H-pyrazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide

Sodium hydride (63 mg, 2.47 mmol) was suspend in DMF (5 ml), and wascooled to 0° C. A solution of 4-bromo-1H-pyrazole (300 mg, 2.06 mmole)in DMF (5 mL) was added dropwise. After stirring for 20 min at 0° C.,methyl 2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate (620 mg, 2.47mmol) was added. The reaction mixture was stirred at room temperaturefor 2 hours. The reaction was quenched with sat. ammonium chloride andextracted into ethyl acetate. The organic layer was washed with water,dried over MgSO₄, concentrated by high vacuum to yield crude compound 5A(492 mg). [M+H] calc'd for C₁₂H₁₇BrN₂O₃ 318.18. found 318.

Compound 5A (492 mg, 1.56 mmol) was dissolved in dioxane (5 ml).Cyclopentylmercaptan (159 mg, 1.56 mmol) was added, followed bydiisopropylethylamine (0.54 ml, 3.12 mmol)tris(dibenzylacetone)dipalladium (71 mg, 0.078 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (90 mg, 0.156 mmol). Thereaction mixture was heated at 100° C. in sealed vial over night. Aftercooling to room temperature, the solution was poured to water, extractedwith ethyl acetate, washed with water, dried over MgSO₄, concentrated byhigh vacuum to crude compound 5B (695 mg). [M+H] calc'd for C₁₇H₂₆N₂O₃S,339.46. found 339.

Compound 5B (695 mg, 2.06 mmol) was dissolved in dichloromethane (20 ml)and cooled to 0° C. m-chloroperoxybenzoic acid (1.84 g, 8.22 mmol) wasadded. After stirring 3 hours at room temperature, the reaction solutionwas diluted with dichloromethane, washed with 1 N NaOH, water, driedover MgSO₄, concentrated by vacuum to afford crude compound 5C (593 mg).[M+H] calc'd for C₁₇H₂₆N₂O₅S, 371.46. found 371.

Compound 5 was synthesized according to the procedure described inconnection with Compound 4. [M+H] calc'd for C₁₉H₂₅FN₄O₄S₂, 457.56.01.found 457. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (m, 3H) 1.50 (m,1H) 1.65 (m, 3H) 1.77 (m, 2H) 2.02 (m, 4H) 2.16 (m, 1H), 2.24 (m, 1H)3.29 (m, 2H) 3.50 (m, 1H) 3.94 (t, J=16, 16 Hz, 2H) 5.13 (m, 1H) 7.08(d, J=4 Hz, 1H) 7.98 (s, 1H) 8.06 (s, 1H)

Compound 6 Methyl2-(3-cyclopentyl-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)propanamido)thiazole-5-carboxylate

Compound 6A (1.663 g, 5.1 mmol), which was generated according to theprocedure described in connection with Compound 1, was dissolved indioxane (15 ml). 2 M LiOH (5.1 ml, 10.2 mmol) was added and the reactionmixture was stirred at room temperature overnight. The reaction solutionwas concentrated, poured to water, acidified with 20% HCl, extractedwith ethyl acetate, dried over Na₂SO₄, concentrated by vacuum to crudecompound 6B (1.494 g). [M+H] calc'd for C₁₄H₂₀N₂O₄S, 313.38. found 313.

Compound 6B (200 mg, 0.64 mmol) was dissolved in NMP (5 ml). Methyl2-aminothioazole-5-carboxylate (184 mg, 1.282 mmol) was added, followedby 2-chloro-1-methylpyridinium iodide (360 mg, 1.41 mmol),diisopropylethylamine (0.25 ml, 1.41 mmol). The reaction mixture washeated at 90° C. in sealed vial overnight. After cooling to roomtemperature, the reaction solution poured to water, extracted with ethylacetate, concentrated. Residue was purified with HPLC to yield compound6 (85 mg). [M+H] calc'd for C₁₉H₂₄N₄O₅S₂, 453.55. found 453. ¹H NMR (400MHz, MeOD). δ ppm 1.23 (m, 6H) 1.60 (m, 6H) 1.82 (m, 1H) 2.20 (m, 1H)2.34 (m, 1H) 2.75 (m, 1H), 3.86 (s, 3H) 5.34 (m, 1H) 7.90 (s, 1H) 8.10(s, 1H) 8.47 (s, 1H)

Compound 72-(3-cyclopentyl-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)propanamido)thiazole-5-carboxylicacid

Compound 6 (67 mg, 0.149 mmol) was dissolved in dioxane (3 ml) and a 2 MLiOH (0.15 ml, 0.3 mmol) solution was added. After stirring at roomtemperature overnight, water (10 ml) was added and the reaction mixturewas acidified with 20% HCl followed by extraction with ethyl acetate.The organic layer was separated, dried and concentrated. This materialwas purified using prep HPLC to afford compound 7 (36.3 mg). [M+H]calc'd for C₁₈H₂₂N₄O₅S₂, 439.52. found 439. ¹H NMR (400 MHz, MeOD). δppm 1.09 (m, 3H) 1.23 (m, 3H) 1.52 (m, 2H) 1.65 (m, 4H) 1.82 (m, 1H)2.19 (m, 1H), 2.34 (m, 1H) 2.75 (m, 1H) 5.35 (m, 1H) 7.90 (s, 1H) 8.06(s, 1H) 8.48 (s, 1H).

Compound 84-chloro-1-(1-(5-chlorothiazol-2-ylamino)-1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)-N-cyclopropyl-1H-pyrazole-3-carboxamide

To 4-chloro-1H-pyrazole-3-carbonyl chloride (0.5 g, 3.03 mmol) indichloromethane (10 ml) at 0° C. was added TEA (0.46 ml, 3.33 mmol)followed by the dropwise addition of cyclopropylamine (0.419 ml, 6.06mmol). The reaction mixture was allowed to warm to room temperature andstirred overnight. The reaction mixture was concentrated in vacuo,extracted into ethyl acetate and washed with sat. bicarbonate and brinesolution. The organic layer was dried over Na₂SO₄, concentrated toobtain 0.55 g of 8A as an oil and used as is in the next step. [M+H]calc'd for C₇H₈ClN₃O, 186.61. found 186.6.

To compound 8A (0.20 g, 1.08 mmol) in DMF (6 ml) was added Cs₂CO₃ (0.373g, 1.14 mmol) and methyl 2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate(0.271 g, 1.08 mmol) in 2 ml of DMF. The reaction mixture was stirredovernight at room temperature, extracted into ethyl acetate and washedwith sat. brine solution. The organic layer was dried over Na₂SO₄ andconcentrated to an oil. This material was purified by silica gel flashcolumn (75% ethyl acetate in hexanes) to obtain 0.3 g of compound 8B.[M+H] calc'd for C₁₆H₂₂ClN₃O₄, 356.82. found 356.80.

Compound 8 was synthesized using methyl2-(4-chloro-3-(cyclopropylcarbamoyl)-1H-pyrazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate(8B) as starting material using the analogous procedure described inconnection with Compound 1. [M+H] calc'd for C₁₈H₂₁Cl₂N₅O₃S, 459.36.found 459.30. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.52-0.60 (m, 2H)0.61-0.71 (m, 2H) 1.13-1.38 (m, 3H) 1.44-1.65 (m, 2H) 1.89-2.05 (m, 1H)2.26-2.38 (m, 1H) 2.76 (td, J=7.33, 4.04 Hz, 1H) 3.19 (q, J=11.79 Hz,2H) 3.71-3.90 (m, 2H) 5.35 (dd, J=10.99, 4.42 Hz, 1H) 7.58 (s, 1H) 8.18(d, J=4.29 Hz, 1H) 8.37 (s, 1H) 13.01 (s, 1H)

Compound 9N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropanesulfonamido)-1H-pyrazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide

Compound 9A was synthesized using 4-nitro-1H-pyrazole and methyl2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate as starting materialusing the analogous procedure described in connection with Compound 1.

Compound 9A (0.37 g) was dissolved in EtOH (15 mL). A catalytic amountof Pd—C was added. The suspension was purged with H₂ gas 3 times, andthen stirred at room temperature under H₂ overnight. The suspension wasthen filtered and the filtrate was concentrated in vacuo to yield 9B(0.121 g). [M+H] calc'd for C₁₂H₁₉N₃O₃, 254.3. found, 254.3.

To the amine 9B (0.120 g) in 10 ml of DCM at 0° C. was added pyridine(0.038 ml), DMAP (0.057 g), followed by the dropwise addition of methanesulfonyl chloride (0.052 ml). The reaction mixture was allowed to warmto room temperature and stirred overnight. The reaction mixture waswashed with water and brine, dried over Na₂SO₄, and concentrated invacuo to obtain intermediate 9C as an oil. [M+H] calc'd for C₁₅H₂₃N₃O₅S,358.4 found, 358.4.

Compound 9 was synthesized using methyl2-(4-(cyclopropanesulfonamido)-1H-pyrazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate(9C) as starting material using the analogous procedure described inconnection with Compound 1. [M+H] calc'd for C₁₇H₂₂ClN₅O₄S₂, 460.97.found 461.0; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.87 (m, 2H) 0.88-0.96(m, 2H) 1.14-1.31 (m, 3H) 1.46 (d, J=10.36 Hz, 1H) 1.59 (d, J=9.35 Hz,1H) 1.92-2.02 (m, 1H) 2.12-2.23 (m, 1H) 2.54-2.57 (m, 1H) 3.09-3.21 (m,3H) 3.74-3.86 (m, 2H) 5.30 (dd, J=10.10, 5.31 Hz, 1H) 7.36 (s, 1H) 7.57(s, 1H) 7.82 (s, 1H) 9.22 (s, 1H) 12.87 (s, 1H)

Compound 10N-(5-chlorothiazol-2-yl)-2-(5-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide

Compound 10A was synthesized using 5-bromo-1H-indazole and methyl2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate as starting materialusing the analogous procedure described in connection with Compound 1. Amixture (˜4:1) of the N-1 vs. N-2 alkylated product was obtained.Purification using flash column chromatography (4:1, hexane:ethylacetate) gave compound 10A.

To methyl2-(5-bromo-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.22g) in 10 ml of DMSO, was added sodium cyclopropanesulfinate (0.23 g),copper iodide (0.01 lg), dimethylethylenediamine (0.013 ml) and K₂CO₃(0.167 g). The reaction was heated at 100° C. overnight. The reactionmixture was extracted into ethyl acetate, washed with water and brine,dried over Na₂SO₄, and concentrated in vacuo to obtain intermediate 10Bas an oil. [M+H] calc'd for C₁₉H₂₄N₂O₅S, 393.47 found, 393.5.

Compound 10 was synthesized using methyl2-(5-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate(10B) as starting material using the analogous procedure described inconnection with Compound 1. [M+H] calc'd for C₂₁H₂₃ClN₄O₄S₂, 496.01.found 496.1. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.01-1.11 (m, 2H)1.18-1.29 (m, 1H) 1.31-1.52 (m, 5H) 1.59-1.71 (m, 1H) 2.31 (ddd,J=14.02, 8.72, 4.80 Hz, 1H) 2.45-2.59 (m, 2H) 3.20 (m, J=19.48, 11.67,11.67, 2.15 Hz, 2H) 3.84-3.97 (m, 2H) 5.51 (dd, J=10.36, 4.80 Hz, 1H)7.26 (s, 1H) 7.61 (d, J=8.84 Hz, 1H) 7.94 (dd, J=8.84, 1.52 Hz, 1H) 8.35(s, 1H) 8.44 (s, 1H)

Compound 10 was subjected to chiral separation on a Berger SFCinstrument using Chiralpak AD-H media eluting with 40% MeOH to affordCompounds 47 and 48.

Compound 70 was obtained using an analogous procedure with the N-2isomer of an indazole related to Compound 10B.

Compound 11N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-((R)-3-oxocyclopentyl)propanamide

Compound 11A was synthesized using 4-bromo-1H-indazole and methyl3-((1R)-3-(benzyloxy)cyclopentyl)-2-bromopropanoate as starting materialusing the analogous procedure described in connection with Compound 1. Amixture of the N-1 vs. N-2 alkylated product was obtained. Purificationusing flash column chromatography (3:1, hexane:ethyl acetate) gavecompound 11A. [M+H] calc'd for C₂₃H₂₆BrN₂O₃, 457.1 found 457.1.

To methyl3-((1R)-3-(benzyloxy)cyclopentyl)-2-(4-bromo-1H-indazol-1-yl)propanoate(0.327 g) in 10 ml of DMSO, was added sodium cyclopropanesulfinate (0.57g), copper iodide (0.085 g), dimethylethylenediamine (0.096 ml). Thereaction was heated at 150° C. overnight. The reaction mixture wascooled and washed with water and brine, dried over Na₂SO₄, andconcentrated in vacuo to afford 11B. [M+H] calc'd for C₂₆H₃₁N₂O₅S,483.19 found 483.2.

5-chlorothiazol-2-amine (0.35 g, 2.04 mmole) was added to a microwavevial followed by DCE (3 mL). The reaction mixture was cooled to 0° C.under a N₂ atmosphere. Trimethyl aluminum (2M in hexanes) (2.0 mmole)was added and when the reaction subsided the cooling bath was removed,the solution was then stirred at RT for 15 min. To this was added asolution of methyl3-((1R)-3-(benzyloxy)cyclopentyl)-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)propanoate11B (0.165 g, 0.34 mmole) in DCE (2 mL) and the reaction mixture washeated in a microwave at 110° C. for 1 h. The reaction was then quenchedwith 1N HCl and extracted 2× with DCM. The organic layers were pooled,dried over Na₂SO₄ and the solvent was removed. This crude residue waspurified by preparative scale HPLC to afford compound 11C as a yellowoil (0.193 g). [M+H] calc'd for C₂₈H₂₉ClN₄O₄S₂, 585.13. found 585.2.

Compound 11 was synthesized by treating compound 11C (0.142 g) with anexcess of TMSI at 50° C. for 0.5 h. The reaction mixture was quenchedwith MeOH, the solvent was the removed in vacuo and the residue wasportioned between EtOAc and NaHCO₃ soln., the organics were dried overNa₂SO₄ and concentrated in vacuo. The crude material was subsequentlyredissolved in DCM and treated with pyridinium chlorochromate 20% onbasic aluminum. After oxidation was complete the reaction mixture wasfiltered through a pad of celite and concentrated. Purification bypreparative scale HPLC afforded compound 11 (0.040 g). [M+H] calc'd forC₂₁H₃₁ClN₄O₄S₂, 493.07. found 493.1. ¹H NMR (MeOD) δ ppm: 8.48 (s, 1H),8.07 (dd, J=8.6, 3.0 Hz, 1H), 7.75 (d, J=7.1 Hz, 1H), 7.64 (dd, J=8.6,7.3 Hz, 1H), 7.30 (s, 1H), 5.59-5.73 (m, 1H), 2.73-2.85 (m, 1H),2.52-2.70 (m, 1H), 2.24-2.42 (m, 1H), 1.76-1.87 (m, 2H), 1.57-1.75 (m,3H), 1.42-1.56 (m, 1H), 1.18-1.35 (m, 3H), 0.98-1.11 (m, 2H).

Compound 122-(4-(cyclopropylsulfonyl)-6-(difluoromethoxy)-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide

Compound 12A was synthesized by treating 4-bromo-1H-indazol-6-ol (1.0 g,4.7 mmol) with TBSCl (0.78 g, 5.2 mmol) and imidazole (0.35 g, 5.2 mmol)in 5 ml of DMF and stirring the solution at RT overnight. The reactionmixture was worked up using standard protecting group introductionprotocol and the resulting orange red oil crystallized on standing (1.2g). This material was dissolved in CH₃CN (10 mL) and treated with Boc₂(0.88 g, 4.03 mmol), Et₃N (0.48 g, 4.8 mmol) and a catalytic amount ofDMAP. The reaction was stirred at RT overnight, concentrated undervacuum and partitioned between DCM and 1N HCl. The organic layer wasdried over MgSO₄ and concentrated. Purification using flash columnchromatography afforded the title material as a clear oil (519 mg, 33%yield) [M+H] calc'd for C₁₈H₂₈BrN₂O₃Si, 427.1 found 427.1.

Compound 12B was synthesized by treating 12A (0.52 g, 1.2 mmol) in THF(5 mL) with 1M TBAF (2.4 mmol) at 0° C. for 15 min. The reaction mixturewas poured into NH₄Cl sat and extracted with EtOAc. The organics weredried over Na₂SO₄ and concentrated under vacuum. The resulting materialwas dried under high vacuum prior to use in the next step. Transfer ofthis compound to a pressure bottle was achieved with 1-2 mL of DMF;followed by the addition of Cs₂CO₃ (0.39 g, 1.2 mmol). This suspensionwas chilled and an excess of difluorobromomethane was condensed into thereaction mixture. The pressure bottle was sealed, allowed to warm to RTand stirred continuously for 2 d. Subsequent warming to 50° C. for 1 dafforded a 70/30 mixture of the product and starting material, which wasseparated with flash column chromatography. This material was treatedwith a 1:1 mixture of TFA/DFCM at RT for 1 h. Removal of solvent andportioning of the residue between EtOAc and sat. NaHCO₃ gave the titlecompound (0.18 g, 57% yield).

Compound 12C was synthesized from 12B (0.18 g, 0.67 mmol) and methyl2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.25 g, 1.0 mmol) usingan analogous procedure described in connection with Compound 1. Thetitle compound (yellow oil) was isolated as a crude N1 & N2 mixture(70/30) with the desired N1 material dominant. The regioisomers wereseparated with flash column chromatography; [M+H] calc'd forC₁₇H₂₀BrF₂N₂O₄, 433.1 found 433.2.

Compound 12D was synthesized from 12C using an analogous proceduredescribed in connection with Compound 10. The title material wasisolated and purified using preparative HPLC; [M+H] calc'd forC₁₉H₂₃F₂N₂O₆S, 445.1 found 445.3.

Compound 12 was synthesized from 12D (0.08 g, 0.17 mmol) which wasdissolved in DCM (5 mL). To this solution was added1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.04 g, 0.3 mmol) at RT andthe mixture was stirred for 30 min. 1-methyl-1H-pyrazol-3-amine (0.03 g,0.3 mmol) was subsequently added along with DIPEA (0.04 g, 0.3 mmol).The solvent was removed under reduced pressure and the residue waspartitioned between EtOAc and sat. bicarbonate soln. The organics weredried and purified by flash column chromatography to afford compound 12(0.044 g). [M+H] calc'd for C₂₃H₂₈F₂N₅O₅S, 524.2. found 524.4. ¹H NMR(MeOD) δ ppm: 0.94-1.13 (m, 2H) 1.22-1.46 (m, 5H) 1.52 (dd, J=9.47, 1.89Hz, 1H) 1.72 (dd, J=9.98, 1.89 Hz, 1H) 2.05-2.29 (m, 1H) 2.54 (ddd,J=14.15, 10.23, 4.17 Hz, 1H) 2.84 (tt, J=7.96, 4.80 Hz, 1H) 3.12-3.29(m, 2H) 3.65 (s, 1H) 3.73-3.80 (m, 3H) 3.80-3.96 (m, 2H) 5.63 (dd,J=10.36, 5.31 Hz, 1H) 6.45 (d, J=2.27 Hz, 1H) 7.42 (d, J=2.27 Hz, 1H)7.54 (d, J=1.77 Hz, 1H) 7.89 (d, J=2.27 Hz, 1H) 8.46 (s, 1H).

Compound 132-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide

Compound 13A: LDA (68 ml, 478 mmol) and THF (500 ml) were cooled to 0°C. while stirring under nitrogen and n-BuLi (192 ml, 478 mmol, 2.5 M inhexanes) was added dropwise. After 30 min, the mixture was cooled to−78° C. (dry ice/acetone bath) and 3,5-difluoropyridine (50 g, 434 mmol)dissolved in 500 ml of THF was added dropwise while maintaining thetemperature below −69° C. After 4 h, methyl formate (54 ml, 868 mmol)dissolved in 135 ml of THF was added dropwise (completed addition in1.25 h). In a separate flask, 1 L sat. NaHCO₃ was cooled to 0° C. whilestirring. The reaction mixture was added to the NaHCO₃ solution whilestirring and the mixture was allowed to warm to room temperature. Theorganic layer was separated and the water layer was extracted with ethylacetate (4×, 250 mL). The combined organic extracts were washed withsat. brine, dried over Na₂SO₄ and concentrated to obtain a dark purpleoil. Purification using flash column chromatography gave 32.5 g (52%yield) of compound 13A.

Compound 13B: To a solution of 3,5-difluoroisonicotinaldehyde (10.15 g,70.60 mmol) in NMP (50 ml) at 0° C. was added anhydrous hydrazine (2.3ml, 70.69 mmol) dropwise. The reaction solution was stirred at R.T. for2 hrs (monitored by LC-MS for completion of reaction to hydrazone). Thereaction mixture was then heated at 140° C. overnight for conversion tothe indazole (monitored by LC-MS for completion of reaction).Cyclopropylsulfinic acid sodium salt (18.1 g, 141.38 mmol) was thenadded to the reaction mixture and it was heated at 180° C. overnight.When reaction was complete (monitored by LC-MS), the reaction mixturewas concentrated using a high vacuum pump to remove NMP and thenextracted into ethyl acetate. The organic layer was washed with waterand any solid obtained was filtered through celite. The combined organiclayers were washed with H₂O, dried over MgSO₄, filtered, andconcentrated in vacuo. The oil was purified by flash columnchromatography (80% EtOAc in hexanes to 100% EtOAc) to yield 5.492 g(54% yield) of compound 13B. [M+H] calc'd for C₉H₉N₃O₂S, 224.2. found,224.25.

Compound 13C: Sodium hydride (557 mg, 22.0 mmol) was suspended in DMF (5ml), and cooled to 0° C. A solution of Compound 13B (3.77 g, 16.92mmole) in DMF (15 mL) was added dropwise to it. After stirring for 20min at 0° C., methyl 2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate(5.52 g, 22.0 mmol) was added dropwise to the reaction mixture and itwas allowed to warm at room temperature and stirred for 2 hours. Thereaction mixture was quenched with sat. ammonium chloride and extractedinto ethyl acetate. The organic layer was washed with water, dried overMgSO₄, filtered, and concentrated under reduced pressure to yield crudecompound 13C (5.94 g; 89% yield). [M+H] calc'd for C₁₈H₂₃N₃O₅S, 394.4.found, 394.46.

Compound 13D: To a suspension of 5-fluorothiazol-2-amine hydrochloride(9.36 g, 60.5 mmole) in DCE (30 mL) at 0° C. under a N₂ atmosphere wasadded trimethyl aluminum (2M in hexanes) (30.3 mL, 60.5 mmole) dropwise.After stirring at room temperature for 30 minutes, a solution ofCompound 13C (5.94 g; 15.12 mmol) in DCE (30 ml) was added dropwise andthe reaction mixture was heated at 100° C. for 2 hours. After cooling to0° C., the reaction mixture was quenched with 1N HCl and extracted 2×with DCM. The organic layers was combined, dried over Na₂SO₄, filteredand concentrated under reduced pressure to yield the crude Compound 13D.

Compounds 13 and 140 were obtained from compound 13D as a TFA salt,after purification using prep HPLC (Waters System: Column is PhenomenexC18, 5μ, 150×50 mm, mobile phase A: 0.05% TFA in H2O and mobile phase Bis 0.035% TFA in acetonitrile, Solvent gradient is 40-55% B); [M+H]calc'd for C₂₀H₂₂FN₅O₄S₂, 480.5. found, 480.55.

Compound 13 was obtained as a free base by concentration of the HPLCfractions, followed by extraction into ethyl acetate and washing withsatd. NaHCO₃. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain compound 13.

Compound 13 was subjected to chiral separation on a Berger SFCinstrument using Chiralpak AD-H media eluting with 40% MeOH to affordCompounds 84 and 85.

Compound 146-(2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamido)nicotinamide

Compound 14A was synthesized using 4-bromo-1H-indazole and methyl2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate as starting materialusing the analogous procedure described in connection with Compound 10.A mixture (˜3:1) of the N-1 vs. N-2 alkylated product was obtained.Purification using flash column chromatography (4:1, hexane:ethylacetate) gave compound 14A.

Compound 14B was synthesized by treating 14A (0.4 g, 1.0 mmol) inTHF-H₂O (5:1, 10 mL) with 1M LiOH (3.0 mmol) at 0° C. for 15 min. andthe mixture was stirred for 18 h at room temperature. The reactionmixture was acidified with 1N HCl and extracted with EtOAc. The organicswere dried over Na₂SO₄ and concentrated under vacuum. The resultingmaterial was dried under high vacuum prior to use in the next step.

Compound 14 was synthesized from 14B (0.15 g, 0.39 mmol) which wasdissolved in NMP (5 mL). To this solution was added 6-aminonicotinamide(0.109 g, 0.79 mmol). 2-chloro-1-methylpyridiniumidodide (0.15 g, 0.58mmol) was subsequently added along with DIPEA (0.092 mL, 0.53 mmol) atRT and the mixture was stirred for 18 h at 80° C. The reaction mixturewas cooled and partitioned between EtOAc and sat. NaCl soln. The organiclayer were dried and purified by prep HPLC (Waters System: Column isSunFire C18, 5μ, 30×75 mm, mobile phase A: 0.05% TFA in H2O and mobilephase B is 0.035% TFA in acetonitrile, Solvent gradient is 30-45% B); toafford compound 14 (158 mg). [M+H] calc'd for C₂₄H₂₈N₅O₅S, 498.3. found498.6. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94-1.13 (m, 2H) 1.13-1.43 (m,5H) 1.43-1.67 (m, 2H) 2.12-2.28 (m, 1H) 2.50 (ddd, J=14.21, 10.42, 5.18Hz, 1H) 2.93-3.22 (m, 3H) 3.79-3.95 (m, 2H) 5.89 (dd, J=9.47, 4.93 Hz,1H) 7.48 (br. s., 1H) 7.61-7.77 (m, 2H) 7.95-8.12 (m, 2H) 8.12-8.28 (m,2H) 8.43 (s, 1H) 8.83 (d, J=1.77 Hz, 1H) 11.32 (s, 1H).

Compound 14 was subjected to chiral separation on a Berger SFCinstrument using Chiralpak AD-H media eluting with 40% MeOH to affordCompounds 107 and 108.

Compound 152-(4-(cyclopropylsulfonyl)-5-methoxy-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide

Compound 15A: A solution of bromine (15.69 g, 0.097 mol) in acetic acid(8.88 ml) was added dropwise to a solution of 3-methyl-4-nitrophenol(14.8 g, 0.097 mol) in acetic acid (118 ml) over 45 min, and the mixturestirred for another 3 h hour. Since the reaction was not complete asmonitored for completeness using LC-MS, 1 ml Bromine in acetic acid (2ml) was added to the reaction mixture, and the mixture was stirredovernight. The solvent was removed under reduced pressure and theresidue was suspended in water and extracted with ethyl acetate. Themixture was filtered through Celite. The organic layer was separated,washed with brine, dried over Na₂SO₄, and concentrated to afford crudecompound Compound 15A (15 g) and the other regioisomer(3-methyl-4-nitro-6-bromophenol) in a 2:1 ratio. The crude compound istaken on to the next step without purification.

Compound 15B: To the crude compound 15A (104 g, 0.45 mol) in acetone(1000 ml), K₂CO₃ (68 g, 0.49 mol) and methyl iodide (74 g, 0.52 mol)were added at room temperature. The mixture was refluxed for 1.5 hour.Since the reaction was not complete as monitored for completeness byLC-MS, K₂CO₃ (325 mesh) (22.6 g, 0.16 mol) and MeI (10 ml, 0.16 mol) wasadded to the reaction mixture, and the mixture was allowed to refluxovernight. The reaction was again monitored for completeness by LC-MS.Additional K₂CO₃ (325 mesh) (8 g, 0.058 mol) and MeI (4 ml) was added tothe reaction mixture, and the mixture allowed to reflux for anotherhour. The reaction mixture was then cooled to room temperature,filtered, and concentrated. The residue was portioned between EtOAc andH₂O. The organic layer was separated, dried and concentrated to yieldcrude compound 15B (152 g) as a brown solid.

Compound 15C: To a solution of compound 15B (76.4 g, 0.311 mol) in DCM(160 ml) was added NH₄VO₃ (2.18 g, 0.0186 mol), P(OPh)₃ (0.964 g,0.00311 mol) and Pt/C (5%) (15.5 g). The mixture was stirred under H₂ at85 psi overnight. The reaction mixture was filtered through Celite andconcentrated to give 64.9 g crude compound 15C. The crude compound 15Ccontaining the other regioisomer (5-bromo-4-methoxy-2-methylaniline) wasseparated at this stage by flash column chromatography (0-100% ethylacetate in hexanes) to afford compound 15C (34.66 g).

Compound 15D: To compound 15C (32.2 g, 0.149 mol) in CHCl₃ (470 ml) wasadded Ac₂O (32.65 ml, 0.345 mol). The reaction mixture was stirred atroom temperature for 40 min. KOAc (4.47 g, 0.0455 mol) and isoamylnitrite (44.3 ml, 0.331 mol) was added to the reaction mixture. Thereaction mixture was refluxed overnight, cooled in an ice bath andneutralized with 1N NaOH. The organic layer was separated from theaqueous layer, washed with brine and dried over Na₂SO₄ and concentrated.The residue was taken up in a methanol (296 ml) and 6N HCl solution (90ml). The reaction mixture was heated to reflux for one hour. Aftercooling, the reaction mixture was concentrated. The solid wasneutralized with a saturated aqueous NaHCO₃ solution, isolated byfiltration, washed with water and dried to afford compound 15D (23 g)

Compound 15E: Compound 15D (12 g, 0.0529 mol) was dissolved in DMF (140mL) and the solution was chilled to 0° C. NaH (2.65 g, 0.0663 mole) wasadded and when the reaction subsided, methyl2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate (15.9 g, 0.0635 mole) wasadded to the reaction mixture. The reaction mixture was then warmed toroom temperature and stirred overnight. When the reaction was completeas monitored by LC-MS (N1:N2 ratio was 3:1), the reaction mixture wascooled in an ice bath, quenched with a small volume of water andextracted into EtOAc. The organic layer was dried over Na₂SO₄, filteredand concentrated to obtain an oil which was purified by flash columnchromatography to afford Compound 15E (7.54 g).

Compound 15G: To compound 15E (7 g, 0.0177 mol) in 48 ml of DMSO wasadded sodium cyclopropanesulfinate (6.93 g, 0.0546 mol), copper iodide(3.46 g, 0.0182 mol) and dimethylethylenediamine (1.96 ml, 0.0182 mol).The reaction was heated at 150° C. for 40 min. The reaction mixture wasthen cooled in an ice bath, diluted with EtOAc and filtered throughcelite. The organic layer was dried over Na₂SO₄ and concentrated toafford a mixture of compound 15F and compound 15G. The residue wasdissolved in MeOH (100 ml) and HCl (6N, 10 ml) was added to it. Thereaction mixture was heated to reflux and stirred overnight. After thereaction mixture was cooled to room temperature, it was concentratedunder vacuum, and extracted into EtOAc. The organic layer was washedwith water and brine, dried over Na₂SO₄, filtered and concentrated toobtain an oil. The crude oil was purified by flash column chromatographyto give compound 15G (2.7 g).

Compound 15: To a solution of 1-methyl-1H-pyrazol-3-amine (2.50 g, 25.78mmol) in DCE (25 ml) at 0° C. under a N₂ atmosphere was added trimethylaluminum (2M in hexanes) (12.89 mL, 25.8 mmole). After 15 min, asolution of compound 15G (2.72 g, 6.46 mmole) in DCE (12 ml) was addedto the reaction mixture and the solution was heated at 90° C. for 2 h.The reaction mixture was then cooled in ice bath, quenched with 1N HCland extracted 2× with EtOAc. The organic layer was dried over Na₂SO₄ andthe crude residue was purified by flash column chromatography(Hexanes/EtOAc, 30%-100%) to afford compound 15 (2.7 g). [M+H] calc'dfor C₂₃H₂₉N₅O₅S, 488. found 488, ¹H NMR (CHLOROFORM-d, 400 MHz): δ=8.72(s, 1H), 8.64 (s, 1H), 7.67 (d, J=9.3 Hz, 1H), 7.30 (d, J=9.1 Hz, 1H),7.22 (d, J=2.5 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 5.27 (dd, J=10.6, 4.8Hz, 1H), 4.07 (s, 3H), 3.82-3.92 (m, 2H), 3.75 (s, 3H), 3.09-3.29 (m,3H), 2.44-2.56 (m, 1H), 2.28 (d, J=5.1 Hz, 1H), 1.42-1.52 (m, 2H),1.29-1.40 (m, 3H), 1.21 (d, J=6.1 Hz, 2H), 0.95-1.09 ppm (m, 2H)

Compound 15 was subjected to chiral separation on a Berger SFCinstrument using Chiralpak OD-H media and eluting with 25% Isopropanolto afford Compounds 109 and 110.

Compound 162-(6-amino-4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide

Compound 16A: To a solution of 2-fluoro-4-iodonicotinaldehyde (3.0 g,11.95 mmol) in ethanol (45 ml) was added hydrazine monohydrate (1.12 g,14.34 mmol) and the reaction mixture was heated at 120° C. in a sealedvial overnight. The reaction mixture was cooled to room temperature, andthen was concentrated under reduced pressure. The residue was treatedwith water (30 ml) and 1 N NaOH (20 ml) and extracted with CHCl₃ (40×4ml). The organic layer was separated, dried over MgSO₄ and concentratedto yield crude compound 16A as solid (2.74 g). [M+H] calc'd for C₆H₄IN₃,246. found 246.

Compound 16B: To a solution of 16A (1.00 g, 4.02 mmol) in DMF (12 ml)was added sodium cyclopropanesulfinate (1.57 g, 12.2 mmol) and thereaction was heated at 120° C. for 4 hours. After cooling to roomtemperature, the reaction mixture was concentrated and the residue wastreated with water, followed by extracted into ethyl acetate. Theorganic layer was separated, dried over MgSO₄ and concentrated underreduced pressure to yield crude 16B (0.98 g). [M+H] calc'd forC₉H₉N₃O₂S, 224. found 224.

Compound 16C was synthesized from compound 16B using an analogousprocedure described in connection with Compound 10 to yield crude 16C assolid (1.496 g, 86%). [M+H] calc'd for C₁₈H₂₃N₃O₅S, 394. found 394.

Compound 16D: To a solution of compound 16C (878 mg, 2.23 mmol) in DCM(10 ml) was added tetrabutylammonium nitrate (1.021 g, 3.35 mmol) andthe solution was cooled to 0° C. Trifluoroacetic anhydride (0.47 ml,3.35 mmol) was then added dropwise to the reaction mixture and it wasstirred at 0° C. for 1.5 h. after which another 1.5 eq. oftetrabutylammonium nitrate and trifluoroacetic anhydride was added tothe reaction mixture at 0° C. and stirred for 1.5 h. The reactionmixture was diluted with DCM and washed with water. The organic layerwas separated, dried over MgSO₄ and concentrated under reduced pressure.The residue obtained was purified by prep. HPLC (Waters System: Columnis Phenomenex C18, 5μ, 150×50 mm, mobile phase A: 0.05% TFA in H2O andmobile phase B is 0.035% TFA in acetonitrile, Solvent gradient is 40-55%B); to yield 16D as solid (176 mg, 18%). [M+H] calc'd for C₁₈H₂₂N₄O₇S,439. found 439.

Compound 16E was synthesized from compound 16D using an analogousprocedure described in connection with Compound 10 to yield crude 16E(233 mg). [M+H] calc'd for C₂₀H₂₁FN₆O₆S₂, 525. found 525.

Compound 16: To a vial charged with ammonium metavanadate (5 mg, 0.032mmol) and triphenylphosphite (2 mg, 0.05 mmol) was added a solution ofcompound 16E (233 mg, 0.54 mmol) in THF (12 ml), followed by a catalyticmount of Pt/C (5%). The reaction mixture was stirred under hydrogen (85psi) for 24 hours. The reaction mixture was then filtered through Celiteand concentrated under reduced pressure to obtain a residue which waspurified via prep. HPLC (Waters System: Column is Phenomenex C18, 5μ,150×50 mm, mobile phase A: 0.05% TFA in H2O and mobile phase B is 0.035%TFA in acetonitrile, Solvent gradient is 40-55% B); to yield compound 16(54 mg). [M+H] calc'd for C₂₀H₂₃FN₆O₄S₂, 496. found 496. ¹H NMR (400MHz, METHANOL-d₄) δ ppm 0.99-1.07 (m, 9H) 1.29-1.42 (m, 22H) 1.47-1.54(m, 4H) 1.71-1.78 (m, 4H) 2.09-2.19 (m, 4H) 2.52-2.63 (m, 5H) 2.90 (tt,J=8.08, 4.80 Hz, 5H) 3.12-3.28 (m, 9H) 3.80-3.90 (m, 9H) 5.86 (dd,J=10.99, 4.42 Hz, 5H) 7.08 (d, J=2.53 Hz, 4H) 8.15 (s, 4H) 8.32 (s, 4H).

Compound 16 was subjected to chiral separation on a Berger SFCinstrument. For this particular compound it was found that usingChiralpak AD-H media eluting with 40% MeOH afforded Compounds 111 and112

Compound 95 was synthesized from compound 16C using an analogousprocedure described in connection with Compound 10. The crude compoundwas purified by prep. HPLC (Waters System: Column is Phenomenex C18, 5μ,150×50 mm, mobile phase A: 0.05% TFA in H2O and mobile phase B is 0.035%TFA in acetonitrile, Solvent gradient is 40-55% B) to yield compound 95.[M+H] calc'd for C₂₁H₂₇N₆O₄S, 459. found 459. ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.08-1.18 (m, 2H) 1.28-1.44 (m, 5H) 1.54 (d, J=9.35Hz, 1H) 1.74 (dd, J=10.11, 1.77 Hz, 1H) 2.17-2.27 (m, 1H) 2.67 (ddd,J=14.21, 10.93, 3.66 Hz, 1H) 2.89 (tt, J=7.86, 4.77 Hz, 1H) 3.10-3.28(m, 2H) 3.76 (s, 3H) 3.85 (dd, J=10.74, 4.93 Hz, 2H) 5.99 (dd, J=10.99,4.67 Hz, 1H) 6.42 (d, J=2.53 Hz, 1H) 7.42 (d, J=2.27 Hz, 1H) 7.69 (d,J=4.80 Hz, 1H) 8.51 (s, 1H) 8.81 (d, 1H)

Compound 192-(6-cyano-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide

Compound 19A: To a solution of 3,5-difluoro-4-formylbenzonitrile (9.76g, 0.058 mol) in N-Methyl-2-pyrrolidinone (100 ml) at 0° C. was addedanhydrous hydrazine (2.06 g, 0.064 mol) and the reaction mixture wasstirred at 0° C. for 1 h. The solution was then allowed to warm to roomtemperature and stirred for 2 h (monitored by LC-MS for completion ofreaction to hydrazone). The reaction mixture was then heated to 180° C.for 4 h. The solution was cooled to room temperature andsodiumcyclopropanesulfinate (9.73 g, 0.076 mol) was added. The reactionmixture was then heated overnight at 180° C. followed by heating at 190°C. for another 5 h. The reaction mixture was cooled to room temperature,diluted with EtOAc and filtered through a pad of Celite. The filtratewas washed with brine solution, dried over Na₂SO₄ and concentrated toobtain a residue which was purified by flash column chromatography toyield compound 19A (8.5 g). [M+H] calc'd for C₁₁H₉N₃O₂S, 248. found 248.

Compound 19B: Compound 19A (4.2 g, 16.99 mmol) was dissolved in DMF (50mL) and the solution was chilled to 0° C. NaH (0.88 g, 22.08 mmol) wasadded and when the reaction subsided, methyl2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate (5.54, 22.08 mmol) wasadded to the reaction mixture. The reaction mixture was then warmed toroom temperature and stirred overnight. When the reaction was completeas monitored by LC-MS (N1:N2 ratio was 3; 1), the reaction mixture wascooled in an ice bath, quenched with a small volume of water andextracted into EtOAc. The organic layer was dried over Na₂SO₄, filteredand concentrated to obtain an oil which was purified by flash columnchromatography to afford the N1 isomer as Compound 19B (1.8 g, 25%)[M+H] calc'd for C₂₀H₂₃N₃O₅S, 418. found 418.

Compound 19: To a solution of 1-methyl-1H-pyrazol-3-amine (5.21 g, 53.7mmol) in DCE (70 ml) at 0° C. under a N₂ atmosphere was added trimethylaluminum (2M in hexanes) (26.8 mL, 53.7 mmole). After 15 min, a solutionof compound 19B (5.6 g, 13.41 mmole) in DCE (15 ml) was added to thereaction mixture and the solution was heated overnight at 90° C. Thereaction mixture was then cooled in ice bath, quenched with 1N HCl andextracted 2× with EtOAc. The organic layer was dried over Na₂SO₄ and thecrude residue was purified by flash column chromatography(Hexanes/EtOAc, 40%-100%) to afford compound 19 as a free base (4.47 g,69%). [M+H] calc'd for C₂₃H₂₆N₆O₄S, 483. found 483. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.60-8.71 (m, 2H), 8.24 (s, 1H), 7.96 (d, J=1.01 Hz,1H), 7.22-7.28 (m, 1H), 6.62 (d, J=2.27 Hz, 1H), 5.45 (dd, J=5.56, 9.85Hz, 1H), 3.84-3.98 (m, 2H), 3.77 (s, 3H), 3.13-3.32 (m, 2H), 2.55-2.67(m, 1H), 2.44-2.55 (m, 1H), 2.35 (dd, J=7.71, 13.77 Hz, 1H), 1.63 (d,J=12.13 Hz, 1H), 1.31-1.58 (m, 6H), 1.06-1.19 (m, 2H)

Compound 19 was also purified via prep. HPLC (Waters System: Column isPhenomenex C18, 5μ, 150×50 mm, mobile phase A: 0.05% TFA in H2O andmobile phase B is 0.035% TFA in acetonitrile, Solvent gradient is 40-55%B); to yield compound 19 as a TFA salt.

Compound 19 was subjected to chiral separation on a Berger SFCinstrument using Chiralpak AD-H media eluting with 20% IPOH to affordCompounds 105 and 106.

Compound 202-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide

Compound 20A: To a solution of amino-pyrazine (3.4 g, 35.8 mmol) in DCE(40 ml) at 0° C. under a N₂ atmosphere was added trimethyl aluminum (2Min hexanes) (17.89 mL, 35.8 mmole). After 15 min, a solution of compound13C (3.52 g, 8.95 mmole) in DCE (20 ml) was added to the reactionmixture and the solution was heated overnight at 90° C. The reactionmixture was then cooled in ice bath, quenched with 1N HCl and extracted2× with EtOAc. The organic layer was dried over Na₂SO₄ and the cruderesidue as compound 20A

Compound 20 was obtained from compound 20A as a TFA salt afterpurification using prep HPLC (Waters System: Column is Phenomenex C18,5μ, 150×50 mm, mobile phase A: 0.05% TFA in H₂O and mobile phase B is0.035% TFA in acetonitrile, Solvent gradient is 40-55% B); [M+H] calc'dfor C₂₁H₂₄N₆O₄S, 457.5. found, 457.55. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.06-1.12 (m, 2H) 1.20-1.37 (m, 5H) 1.50 (d, J=11.62 Hz, 1H) 1.66 (d,J=11.12 Hz, 1H) 2.25-2.35 (m, 1H) 2.52-2.58 (m, 1H) 3.04-3.17 (m, 3H)3.71-3.83 (m, 2H) 6.06 (dd, J=10.11, 5.31 Hz, 1H) 8.40 (d, J=2.53 Hz,1H) 8.42-8.46 (m, 1H) 8.55 (s, 1H) 8.70 (s, 1H) 9.24 (d, J=1.26 Hz, 1H)9.68 (s, 1H).

Compound 20 was obtained as a free base after purification using prepHPLC (Waters System: Column is Phenomenex C18, 5μ, 150×50 mm, mobilephase A: 10 mM NH₄HCO₃ in H₂O and mobile phase B is 10 mM NH₄HCO₃ in 80%acetonitrile, Solvent gradient is 30-35% B).

Compound 20 was subjected to chiral separation on a Berger SFCinstrument using Chiralpak AD-H media eluting with 40% MeOH to affordCompounds 171 and 172.

Compound 214-(cyclopropylsulfonyl)-1-(1-(5-fluorothiazol-2-ylamino)-1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)-1H-indazole-6-carboxylicacid

A solution of2-(6-cyano-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide120 (0.06 g, 0.11 mmol) in EtOH (5 mL) was added to a microwave vialfollowed by 3N NaOH (1 mL) and the mixture was heated at 100° C. for 40min. The solvent was removed under vacuum and the residue waspartitioned between 1N HCl and EtOAc. The organic layer was dried overNa₂SO₄ to give the crude carboxylic acid 21. [M+H] calc'd forC₂₂H₂₄FN₄O₆S₂, 523.1. found 523.3.

4-(cyclopropylsulfonyl)-1-(1-(5-fluorothiazol-2-ylamino)-1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)-1H-indazole-6-carboxylicacid 21 (0.1 g, 0.19 mmol), diphenyl phosphorazidate (0.05 g, 0.19mmol), triethylamine (0.03 g, 0.3 mmol), and tBuOH (0.016 g, 0.21 mmol)were combined in toluene (10 mL) and refluxed for 2 h. The solvent wasremoved and the residue treated with TFA/DCM (1/1) for 15 min. Themixture was concentrated under reduced pressure and purified using prepHPLC (Waters System: Column is Phenomenex C18, 5μ, 150×50 mm, mobilephase A: 0.05% TFA in H₂O and mobile phase B is 0.035% TFA inacetonitrile) to give Compound 142 as a reddish brown solid (50 mg);[M+H] calc'd for C₂₁H₂₅FN₅O₄S₂, 494.1. found 494.4.

Compound 22 Methyl2-(5-chloro-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoateCompound 23 methyl2-(7-chloro-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate

3-chloro-2,6-difluorobenzaldehyde (0.22 g, 1.23 mmol) and sodiumcyclopropanesulfinate (0.19 g, 1.35 mmol) were combined in NMP (3 mL)and heated at 140° C. for 0.5 h. The reaction mixture was diluted withMeOH and purified using HPLC to give a mixture of5-chloro-4-(cyclopropylsulfonyl)-1H-indazole 22A and7-chloro-4-(cyclopropylsulfonyl)-1H-indazole 22 B as a white solid (0.14g); [M+H] calc'd for C₁₀H₁₀ClN₂O₂S, 257.0. found 257.1. ¹HNMR analysisconfirmed the mixture of regioisomers in an approximate 1:1 ratio.

The mixture of 22A and 22 B (0.14 g, 0.54 mmol) was dissolved in DMF (4mL) and the solution was chilled to 0° C. NaH (0.02 g, 0.65 mmol) wasadded and, when the reaction subsided, methyl2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.20, 0.81 mmol) wasadded to the reaction mixture. The reaction mixture was then warmed toroom temperature and stirred for 1 h. The reaction was quenched with asmall volume of MeOH and concentrated under vacuum. The residue wasportioned between EtOAc and 1N HCl. The organic layer was dried overNa₂SO₄, filtered and purified by flash column chromatography to affordcompounds 22C and 22D as a clear oil (0.41 g); [M+H] calc'd forC₁₉H₂₄ClN₂O₅S, 427.1. found 427.3. The mixture of isomers was used as isin the next step.

Compounds 22 and 23: To a solution of 5-fluorothiazol-2-amine (0.29 g,1.9 mmol) in DCE (5 ml) at 0° C. under a N₂ atmosphere was addedtrimethyl aluminum (2M in hexanes) (1.9 mmol). After 15 min, a solutionof Compounds 22C and 22D (0.41 g, 0.96 mmole) in DCE (3 ml) was added tothe reaction mixture and the solution was heated in a microwave oven at100° C. for 1 h. The reaction mixture was then cooled in an ice bath,quenched with 1N HCl and extracted 2× with EtOAc. The organic layer wasdried over Na₂SO₄ and the crude residue was purified by flash columnchromatography using (DCM/MeOH, 0%-10%) to afford pure compounds 22 and23. Compound 22: [M+H] calc'd for C₂₁H₂₃ClFN₄O₄S₂, 513.1. found 513.2;¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96-1.14 (m, 2H) 1.28-1.48 (m, 5H)1.54 (br. s., 1H) 1.71 (d, J=7.58 Hz, 1H) 2.32-2.60 (m, 3H) 3.19-3.37(m, 2H) 3.78-4.06 (m, 2H) 5.42 (dd, J=9.22, 6.19 Hz, 1H) 7.08 (br. s.,1H) 7.45-7.60 (m, 1H) 7.68 (d, J=7.58 Hz, 1H) 8.60 (s, 1H). Compound 23[M+H] calc'd for C₂₁H₂₃ClFN₄O₄S₂, 513.1. found 513.2; ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.93-1.20 (m, 1H) 1.30-1.60 (m, 5H) 1.67 (br. s.,3H) 2.16-2.38 (m, 1H) 2.46-2.74 (m, 2H) 3.17-3.44 (m, 2H) 3.79-4.01 (m,2H) 6.49 (br. s., 1H) 7.00 (d, J=2.53 Hz, 1H) 7.60 (dd, J=7.83, 4.04 Hz,1H) 7.67-7.80 (m, 1H) 8.72 (s, 1H).

In addition to the foregoing, the above reaction schemes and variationsthereof can be used to prepare the following.

Ex. Structure Method LCMS NMR data 24

  2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 1 [M + H] calc'd for C₂₁H₂₆N₅O₅ S₂,492.13; found 492.0 ¹H NMR (400 MHz, MeOD) δ ppm 1.00- 1.14 (m, 2 H)1.16- 1.47 (m, 6 H) 1.66- 1.84 (m, 2 H) 2.15 (br. s., 1 H) 2.32 (dd, J =14.40, 6.82 Hz, 1 H) 2.63-2.87 (m, 1 H) 3.77 (s, 3 H) 3.85-3.98 (m, 4 H)5.47 (dd, J = 10.23, 5.43 Hz, 1 H) 6.84 (d, J = 8.84 Hz, 1 H) 7.90-7.95(m, 1 H) 8.51 (s, 1 H). 25

  (R)-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpds. 2 and 3 [M + H] calc'd forC₂₁H₂₆N₅O₅ S₂, 492.13; found 492.0 ¹H NMR (400 MHz, MeOD) δ ppm 1.00-1.14 (m, 2 H) 1.16- 1.47 (m, 6 H) 1.66- 1.84 (m, 2 H) 2.15 (br. s., 1 H)2.32 (dd, J = 14.40, 6.82 Hz, 1 H) 2.63-2.87 (m, 1 H) 3.77 (s, 3 H)3.85-3.98 (m, 4 H) 5.47 (dd, J = 10.23, 5.43 Hz, 1 H) 6.84 (d, J = 8.84Hz, 1 H) 7.90-7.95 (m, 1 H) 8.51 (s, 1 H). 26

  (S)-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpds. 2 and 3 [M + H] calc'd forC₂₁H₂₆N₅O₅ S₂, 492.13; found 492.0 ¹H NMR (400 MHz, MeOD) δ ppm 1.00-1.14 (m, 2 H) 1.16- 1.47 (m, 6 H) 1.66- 1.84 (m, 2 H) 2.15 (br. s., 1 H)2.32 (dd, J = 14.40, 6.82 Hz, 1 H) 2.63-2.87 (m, 1 H) 3.77 (s, 3 H)3.85-3.98 (m, 4 H) 5.47 (dd, J = 10.23, 5.43 Hz, 1 H) 6.84 (d, J = 8.84Hz, 1 H) 7.90-7.95 (m, 1 H) 8.51 (s, 1 H). 27

  2-(4-(cyclopropylsulfonyl)-3,5-dimethyl-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 4 [M + H] calc'd forC₁₉H₂₆FN₄ O₄S₂, 457.13; found 457 1H NMR (400 MHz, CHLOROFORM-d) δ ppm1.03 (d, J = 8.08 Hz, 2 H) 1.21- 1.45 (m, 5 H) 1.50- 1.63 (m, 2 H) 2.09-2.31 (m, 2 H) 2.48 (d, J = 3.28 Hz, 1 H) 2.51 (s, 3 H) 2.54 (s, 3 H)3.33 (d, J = 9.60 Hz, 2 H) 3.87-4.01 (m, 2 H) 4.96 (dd, J = 9.35, 5.81Hz, 1 H) 7.06 (d, J = 2.78 Hz, 1 H) 28

  2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamideSee Cmpd. 4 [M + H] calc'd for C₁₇H₂₂FN₄ O₄S₂, 429.10, found 429 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.09 (dq, J = 7.86, 2.43 Hz, 2 H)1.27-1.46 (m, 5 H) 1.53 (d, J = 9.35 Hz, 1 H) 1.68 (d, J = 11.87 Hz, 1H) 2.23 (d, J = 14.15 Hz, 1 H) 2.07-2.31 (m, 1 H) 2.51-2.62 (m, 1 H)3.33 (dd, J = 11.37, 2.27 Hz, 2 H) 3.95 (t, J = 11.87 Hz, 2 H) 5.19 (dd,J = 9.73, 5.68 Hz, 1 H) 6.40 (br.s., 1H) 7.11 (d, J = 2.53 Hz, 1 H) 7.94(s, 1 H) 8.09 (s, 1 H) 29

  2-(4-(4-chlorophenylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetra- hydro-2H-pyran-4-yl)propanamideSee Cmpd. 4 [M + H] calc'd for C₂₀H₂₁ClF N₄O₄S₂, 499.06, found 499 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 br. s., 2 H) 1.34 (d, J = 4.29Hz, 1 H) 1.48 (br. s., 1 H) 1.62 (br. s., 1 H) 2.16 (d, J = 6.57 Hz, 2H) 3.23- 3.34 (m, 2 H) 3.93 (dd, J = 16.42, 11.87 Hz, 2 H) 5.11 (dd, J =9.47, 6.19 Hz, 1 H) 5.50 (br.s., 1 H) 7.08 (d, J = 2.78 Hz, 1 H) 7.51(d, J = 8.59 Hz, 2 H) 7.87-7.93 (m, 3 H) 8.10 (s, 1 H) 30

  2-(4-(4-chlorophenylsulfonyl)-1H-pyrazol-1-yl)-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 4 [M + H] calc'd for C₂₄H₂₅ClN₅O₅S₂, 562.09, found 562 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (t, J= 10.11 Hz, 2 H) 1.36 (br. s., 1 H) 1.50 (br. s., 1 H) 1.65 (br. s., 1H) 2.24 (d, J = 4.55 Hz, 1 H) 2.21 (t, J = 6.06 Hz, 1 H) 3.27- 3.36 (m,2 H) 4.00 (s, 3H), 3.87-3.98 (m, 2H) 5.17 (dd, J = 9.35, 6.06 Hz, 1 H)6.87 (d, J = 8.84 Hz, 1 H) 7.51 (d, J = 8.34 Hz, 2 H) 7.86-7.93 (m, 3 H)7.95 (s, 1 H) 8.11 (s, 1 H) 31

  (R)-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamideSee Cmpds. 2 and 3 [M + H] calc'd for C₁₇H₂₂FN₄ O₄S₂, 429.10, found 4291H NMR (400 MHz, CHLOROFORM-d) 6 ppm 1.09 (dq, J = 7.86, 2.43 Hz, 2 H)1.27-1.46 (m, 5 H) 1.53 (d, J = 9.35 Hz, 1 H) 1.68 (d, J = 11.87 Hz, 1H) 2.23 (d, J = 14.15 Hz, 1 H) 2.07-2.31 (m, 1 H) 2.51-2.62 (m, 1 H)3.33 (dd, J = 11.37, 2.27 Hz, 2 H) 3.95 (t, J = 11.87 Hz, 2 H) 5.19 (dd,J = 9.73, 5.68 Hz, 1 H) 6.40 (br.s., 1H) 7.11 (d, J = 2.53 Hz, 1 H) 7.94(s, 1 H) 8.09 (s, 1 H) 32

  (S)-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamideSee Cmpds. 2 and 3 [M + H] calc'd for C₁₇H₂₂FN₄ O₄S₂, 429.10, found 4291H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.09 (dq, J = 7.86, 2.43 Hz, 2 H)1.27-1.46 (m, 5 H) 1.53 (d, J = 9.35 Hz, 1 H) 1.68 (d, J = 11.87 Hz, 1H) 2.23 (d, J = 14.15 Hz, 1 H) 2.07-2.31 (m, 1 H) 2.51-2.62 (m, 1 H)3.33 (dd, J = 11.37, 2.27 Hz, 2 H) 3.95 (t, J = 11.87 Hz, 2 H) 5.19 (dd,J = 9.73, 5.68 Hz, 1 H) 6.40 ( br.s., 1H) 7.11 (d, J = 2.53 Hz, 1 H)7.94 (s, 1 H) 8.09 (s, 1 H) 33

  N-(5-chlorothiazol-2-yl)-3-cyclopentyl-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl) pronanamide See Cmpd. 4 [M + H]calc'd for C₁₇H₂₂ClN₄ O₃S₂, 429.07, found 429 ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.15 (m, 4H) 1.36 (m, 2H) 1.59 (m, 6) 1.79 (m, 1H)2.29 (m, 2H) 2.56 (m, 1H), 5.03 (m, 1H) 7.35 (s, 1H) 7.99 (s, 1H) 8.06(m, 1H) 34

  3-cyclopentyl-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2- yl)propanamide See Cmpd. 4 [M +H] calc'd for C₁₇H₂₂FN₄ O₃S₂, 413.50, found 413 ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.13 (m, 4H) 1.37 (m, 2H) 1.57 (m, 6H) 1.79 (m, 1H)2.25 (m, 2H) 2.55 (m, 1H) 5.02 (m, 1H) 7.14 (s, 1H) 7.97 (s, 1H) 8.17(s, 1H) 35

  (R)-3-cyclopentyl-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2- yl)propanamide See Cmpd. 4 [M +H] calc'd for C₁₇H₂₂FN₄ O₃S₂ 413.50; found 413.36 ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.13 (m, 4H) 1.37 (m, 2H) 1.57 (m, 6H) 1.79 (m, 1H)2.25 (m, 2H) 2.55 (m, 1H) 5.02 (m, 1H) 7.14 (s, 1H) 7.97 (s, 1H) 8.17(s, 1H) 36

  (S)-3-cyclopentyl-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2- yl)propanamide See Cmpd. 4 [M +H] calc'd for C₁₇H₂₂FN₄ O₃S₂ 413.50; found 413.36 ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.13 (m, 4H) 1.37 (m, 2H) 1.57 (m, 6H) 1.79 (m, 1H)2.25 (m, 2H) 2.55 (m, 1H) 5.02 (m, 1H) 7.14 (s, 1H) 7.97 (s, 1H) 8.17(s, 1H) 37

  2-(4-(cyclopentylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran- 4-yl)propanamide SeeCmpd. 5 [M + H] calc'd for C₁₉H₂₆FN₄ O₄S₂ 457.56, found 457 ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 1.34 (m, 3H) 1.50 (m, 1H) 1.65 (m, 3H) 1.77 (m,2H) 2.02 (m, 4H) 2.16 (m, 1H), 2.24 (m, 1H) 3.29 (m, 2H) 3.50 (m, 1H)3.94 (t, J = 16, 16 Hz, 2H) 5.13 (m, 1H) 7.08 (d, J = 4 Hz, 1H) 7.98 (s,1H) 8.06 (s, 1H) 38

  (R)-N-(5-chlorothiazol-2-yl)-3-cyclopentyl-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl) propanamide See Cmpd. 4 [M + H]calc'd for C₁₇H₂₂ClN₄ O₃S₂ 429.96, found 429.36 ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.15 (m, 4H) 1.36 (m, 2H) 1.59 (m, 6) 1.79 (m, 1H)2.29 (m, 2H) 2.56 (m, 1H), 5.03 (m, 1H) 7.35 (s, 1H) 7.99 (s, 1H) 8.06(m, 1H) 39

  (S)-N-(5-chlorothiazol-2-yl)-3-cyclopentyl-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl) propanamide See Cmpd. 4 [M + H]calc'd for C₁₇H₂₂ClN₄ O₃S₂ 429.96, Found 429.3 ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.15 (m, 4H) 1.36 (m, 2H) 1.59 (m, 6) 1.79 (m, 1H)2.29 (m, 2H) 2.56 (m, 1H), 5.03 (m, 1H) 7.35 (s, 1H) 7.99 (s, 1H) 8.06(m, 1H) 40

  (R)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide See Cmpds. 2and 3 [M + H] calc'd for C₁₇H₂₂ClN₄ O₄S₂, 445.07; found 445.2. 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 0.93-1.75 (m, 9 H) 2.19 (br. s., 2 H) 2.55(br. s., 1 H) 3.31 (br. s., 2 H) 3.94 (br. s., 2 H) 5.10 (br. s., 1 H)7.32 (s, 1 H) 8.01 (d, J = 9.35 Hz, 2 H) 10.35 (bs, 1 H) 41

  N-(5-fluorothiazol-2-yl)-2-(4-(methylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide See Cmpd 10 [M +H] calc'd for C₁₉H₂₁FN₄ O₄S₂ 454, found 454 ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.21-1.42 (m, 3 H) 1.42-1.49 (m, 1 H) 1.66-1.74 (m, 1H) 2.13-2.22 (m, 1 H) 2.49-2.58 (m, 1 H) 3.13-3.26 (m, 2 H) 3.29 (br.s., 3 H) 3.78-3.89 (m, 2 H) 5.65 (dd, J = 10.61, 4.80 Hz, 1 H) 7.08 (d,J = 2.53 Hz, 1 H) 7.30-7.41 (m, 2 H) 7.67 (d, J = 8.08 Hz, 1 H) 8.11 (s,1 H) 42

  (S)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide See Cmpds. 2and 3 [M + H] calc'd for C₁₇H₂₂ClN₄ O₄S₂, 445.07; found 445.2. 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 0.93-1.75 (m, 9 H) 2.19 (br. s., 2 H) 2.55(br. s., 1 H) 3.31 (br. s., 2 H) 3.94 (br. s., 2 H) 5.10 (br. s., 1 H)7.32 (s, 1 H) 8.01 (d, J = 9.35 Hz, 2 H) 10.35 (bs, 1 H) 43

  (R)-2-(4-(cyclopentylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran- 4-yl)propanamide SeeCmpd. 5 [M + H] calc'd for C₁₉H₂₆FN₄ O₄S₂ 457.56, found 457 ¹H NMR (400MHz, CHLOROFORM-d). δ ppm 1.34 (m, 3H) 1.50 (m, 1H) 1.65 (m, 3H) 1.77(m, 2H) 2.02 (m, 4H) 2.16 (m, 1H), 2.24 (m, 1H) 3.29 (m, 2H) 3.50 (m,1H) 3.94 (t, J = 16, 16 Hz, 2H) 5.13 (m, 1H) 7.08 (d, J = 4 Hz, 1H) 7.98(s, 1H) 8.06 (s, 1H) 44

  (S)-2-(4-(cyclopentylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran- 4-yl)propanamide SeeCmpd. 5 [M + H] calc'd for C₁₉H₂₆FN₄ O₄S₂ 457.56, found 457 ¹H NMR (400MHz, CHLOROFORM-d). δ ppm 1.34 (m, 3H) 1.50 (m, 1H) 1.65 (m, 3H) 1.77(m, 2H) 2.02 (m, 4H) 2.16 (m, 1H), 2.24 (m, 1H) 3.29 (m, 2H) 3.50 (m,1H) 3.94 (t, J = 16, 16 Hz, 2H) 5.13 (m, 1H) 7.08 (d, J = 4 Hz, 1H) 7.98(s, 1H) 8.06 (s, 1H) 45

  N-(5-chloropyridin-2-yl)-2-(4-(cyclopropyl-sulfonyl)-1H-pyrazol-1-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamide SeeCmpd. 4 [M + H] calc'd for C₁₉H₂₄ClN₄ O₄S, 439.11, found 439 1H NMR (400MHz, CHLOROFORM-d) δ ppm 1.08 (dd, J = 8.08, 2.02 Hz, 2H) 1.30-1.44 (m,1 H) 1.36 (dd, J = 4.42, 2.15 Hz, 4 H) 1.53 (d, J = 9.09 Hz, 1 H) 1.68(d, J = 9.85 Hz, 1 H) 2.19 (t, J = 6.32 Hz, 1 H) 2.25 (dd, J = 9.85,4.04 Hz, 1 H) 2.57 (ddd, J = 7.96, 4.80, 3.16 Hz, 1 H) 3.31 (td, J =11.24, 8.08 Hz, 1 H) 3.25-3.37 (m, 1 H) 3.88-4.00 (m, 2 H) 5.12 (dd, J =9.73, 5.68 Hz, 1 H) 7.74 (dd, J = 8.84, 2.53 Hz, 1 H) 7.98 (s, 1 H) 8.11(s, 1 H) 8.20 (d, J = 8.84 Hz, 1 H) 8.24 (d, J = 2.27 Hz, 1 H) 9.66 (br.s., 1 H) 46

  2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamide See Cmpd. 4 [M +H] calc'd for C₁₈H₂₄N₅ O₄S, 406.15, found 406 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.09 (dd, J = 7.71, 1.64 Hz, 2 H) 1.29-1.47 (m, 5 H)1.54 (br. s., 1 H) 1.66 (br. s., 1 H) 2.14- 2.38 (m, 2 H) 2.51- 2.63 (m,1 H) 3.23- 3.42 (m, 2 H) 3.87- 4.03 (m, 2 H) 5.07 (dd, J = 9.60, 5.56Hz, 1 H) 8.03 (d, J = 6.57 Hz, 2 H) 8.32 (s, 1 H) 8.42 (d, J = 2.27 Hz,1 H) 9.27 (br. s., 1 H) 9.50 (s, 1 H) 47

  (R)-N-(5-chlorothiazol-2-yl)-2-(5-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4- yl)pronanamide See Cmpd. 10[M + H] calc'd for C₂₁H₂₄ClN₄ O₄S₂ 496.01, found 496.1 48

  (S)-N-(5-chlorothiazol-2-yl)-2-(5-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide See Cmpd. 10[M + H] calc'd for C₂₁H₂₄ClN₄ O₄S₂ 496.01, found 496.1 49

  2-(4-(tert-butylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamide See Cmpd. 4[M + H] calc'd for C₁₈H₂₆FN₄ O₄S₂, 445.13, found 445.3 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.29-1.45 (m, 3 H) 1.38 (s, 9 H) 1.51 (d, J = 2.27Hz, 1 H) 1.64 (d, J = 11.62 Hz, 1 H) 2.04- 2.29 (m, 2 H) 3.14- 3.35 (m,2 H) 3.80- 4.02 (m, 2 H) 5.12 (dd, J = 9.85, 5.81 Hz, 1 H) 7.12 (d, J =2.78 Hz, 1 H) 7.95 (s, 1 H) 8.03 (s, 1 H) 50

  2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(3-oxocyclopentyl) propanamide See Cmpd. 4 [M + H]calc'd for C₁₇H₂₀FN₄ O₄S₂ 427.08, found 427.1 51

  N-(5-chlorothiazol-2-yl)-2-(5-(cyclopropylsulfonyl)-2H-indazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M +H] calc'd for C₂₁H₂₄ClN₄ O₄S₂ 496.01, found 496.1 ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.00-1.13 (m, 2 H) 1.20-1.64 (m, 7 H) 1.76 (d, J =12.38 Hz, 1 H) 2.27- 2.42 (m, 1 H) 2.43- 2.60 (m, 2 H) 3.30 (t, J =10.86 Hz, 2 H) 3.87-4.08 (m, 2 H) 5.57 (dd, J = 9.73, 5.18 Hz, 1 H) 7.32(br. s., 1 H) 7.70-7.82 (m, 1 H) 7.87 (d, J = 9.09 Hz, 1 H) 8.42 (d, J =5.56 Hz, 2 H) 52

  (R)-2-(4-(tert-butylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamide SeeCmpds. 2 and 3 [M + H] calc'd for C₁₈H₂₆FN₄ O₄S₂, 445.13, found 445.3 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.29-1.45 (m, 3 H) 1.38 (s, 9 H) 1.51(d, J = 2.27 Hz, 1 H) 1.64 (d, J = 11.62 Hz, 1 H) 2.04- 2.29 (m, 2 H)3.14- 3.35 (m, 2 H) 3.80- 4.02 (m, 2 H) 5.12 (dd, J = 9.85, 5.81 Hz, 1H) 7.12 (d, J = 2.78 Hz, 1 H) 7.95 (s, 1 H) 8.03 (s, 1 H) 53

  (S)-2-(4-(tert-butylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluoruthiazol-2-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamide See Cmpds.2 and 3 [M + H] calc'd for C₁₈H₂₆FN₄ O₄S₂, 445.13, found 445.3 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.29-1.45 (m, 3 H) 1.38 (s, 9 H) 1.51 (d,J = 2.27 Hz, 1 H) 1.64 (d, J = 11.62 Hz, 1 H) 2.04- 2.29 (m, 2 H) 3.14-3.35 (m, 2 H) 3.80- 4.02 (m, 2 H) 5.12 (dd, J = 9.85, 5.81 Hz, 1 H) 7.12(d, J = 2.78 Hz, 1 H) 7.95 (s, 1 H) 8.03 (s, 1 H) 54

  (S)-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-((R)-3-oxocyclopentyl) propanamide See Cmpd.4 [M + H] calc'd for C₁₇H₂₀FN₄ O₄S₂ 427.08, found 427.1 55

  (S)-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-((S)-3-oxocyclopentyl) propanamide See Cmpd.4 [M + H] calc'd for C₁₇H₂₀FN₄ O₄S₂ 427.08, found 427.1 56

  (R)-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-((R)-3-oxocyclopentyl) propanamide See Cmpd.4 [M + H] calc'd for C₁₇H₂₀FN₄ O₄S₂ 427.08, found 427.1 57

  2-(3-cyclopentyl-2-(4-(cyclopropylsulfonyl)-1H-pyrazol-1-yl)propanamido)thiazole-5-carboxamide See Cmpds. 6 and 7 [M +H] calc'd for C₁₈H₂₄N₅O₄ S₂ 438.54, found 438 ¹H NMR (400 MHz, DMSO-d6).δ ppm 1.06 (m, 4H) 1.27 (m, 1H) 1.56 (m, 6H) 2.11 (m, 1H) 2.33 (m, 1H)2.84 (m, 1H), 3.75 (s, 2H) 5.36 (m, 1H) 7.95 (s, 1H) 8.08 (s, 1H) 8.63(s, 1H) 58

  (R)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopentylsulfonyl)-1H-pyrazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide See Cmpd. 5[M + H] calc'd for C₁₉H₂₆ClN₄ O₄S₂ 474.01, found 474 ¹H NMR (400 MHz,CHLOROFORM-d). δ ppm 1.34 (m, 3H) 1.50 (m, 1H) 1.65 (m, 3H) 1.77 (m, 2H)2.02 (m, 4H) 2.19 (m, 2H), 3.29 (m, 2H) 3.52 (m, 1H) 3.95 (t, J = 12, 12Hz, 2H) 5.16 (m, 1H) 7.32 (d, J = 4 Hz, 1H) 7.98 (s, 1H) 8.06 (s, 1H) 59

  N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropyl-sulfonyl)-1H-indazol-1-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamide SeeCmpd. 10 [M + H] calc'd for C₂₁H₂₄ClN₄ O₄S₂ 496.01, found 496.1 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.00-1.12 (m, 2 H) 1.14-1.38 (m, 5 H) 1.45 (br.s., 1 H) 1.60 (br. s., 1 H) 2.26 (d, J = 6.57 Hz, 1 H) 2.46 (br. s., 1H) 2.91-3.21 (m, 3 H) 3.68-3.84 (m, 2 H) 5.87 (dd, J = 9.98, 4.93 Hz, 1H) 7.56 (s, 1 H) 7.63-7.76 (m, 2 H) 8.18 (d, J = 8.34 Hz, 1 H) 8.45 (s,1 H) 60

  N-(5-chlorothiazol-2-yl)-2-(6-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide See Cmpd. 10[M + H] calc'd for C₂₁H₂₄ClN₄ O₄S₂ 496.01, found 496.1 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.00-1.09 (m, 2 H) 1.12-1.37 (m, 5 H) 1.45 (d, J = 8.08Hz, 1 H) 1.60 (d, J = 12.13 Hz, 1 H) 2.21-2.33 (m, 1 H) 2.35-2.47 (m, 1H) 2.83-2.94 (m, 1 H) 3.00-3.17 (m, 2 H) 3.70-3.85 (m, 2 H) 5.93 (dd, J= 9.60, 5.31 Hz, 1 H) 7.56 (s, 1 H) 7.64-7.72 (m, 1 H) 8.08 (d, J = 8.59Hz, 1 H) 8.41 (d, J = 10.86 Hz, 2 H) 61

  3-cyclopentyl-2-(4-(cyclopropylsulfonyl)-1H-indazol-1yl)-N-(pyrazin-2-yl)propanamide See Cmpd. 10 [M + H] calc'd forC₂₂H₂₆N₅ O₃S 440.53; found 440 ¹H NMR (400 MHz, MeOD). δ ppm 1.06 (m,3H) 1.29 (m, 3H) 1.43 (m, 2H) 1.60 (m, 4H) 1.74 (m, 1H) 2.31 (m, 1H)2.64 (m, 1H) 2.81 (m, 1H) 5.64 (m, 1H) 7.74 (d, J = 4 Hz, 1H) 8.11 (d, J= 8 Hz, 1H) 8.30 (s, 1H) 8.34 (s, 1H) 8.50 (s, 1H) 62

  3-cyclopentyl-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)propanamide See Cmpd. 10 [M + H] calc'dfor C₂₁H₂₄FN₄ O₃S₂ 463.56; found 463 ¹H NMR (400 MHz, MeOD). δ ppm 1.07(m, 3H) 1.29 (m, 3H) 1.45 (m, 3H) 1.60 (m, 3H) 1.74 (m, 1H) 2.29 (m, 1H)2.60 (m, 1H) 2.80 (m, 1H) 5.64 (m, 1H) 7.09 (d, J = 4 Hz, 1H) 7.64 (t, J= 8, 8 Hz, 1H) 7.74 (d, J = 8 Hz, 1H) 8.09 (d, J = 12 Hz, 1H) 8.47 (s,1H) 63

  (R)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropyl-sulfonyl)-1H-indazol-1-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamide SeeCmpd. 10 [M + H] calc'd for C₂₁H₂₄ClN₄ O₄S₂ 496.01, found 496.1 64

  (S)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclo-propylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M + H] calc'd forC₂₁H₂₄ClN₄ O₄S₂ 496.01, found 496.1 65

  2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamide See Cmpd. 10[M + H] calc'd for C₂₂H₂₆N₅ O₄S 456.53, found 456.5 ¹H NMR (400 MHz,MeOD) δ ppm 0.91- 1.03 (m, 2 H) 1.16- 1.35 (m, 5 H) 1.38- 1.47 (m, 1 H)1.59- 1.70 (m, 1 H) 2.10- 2.21 (m, 1 H) 2.47- 2.59 (m, 1 H) 2.72 (tt, J= 7.89, 4.74 Hz, 1 H) 3.05-3.18 (m, 2 H) 3.68-3.83 (m, 2 H) 5.71 (dd, J= 10.61, 4.80 Hz, 1 H) 7.51-7.59 (m, 1 H) 7.63-7.69 (m, 1 H) 8.02 (d, J= 8.59 Hz, 1 H) 8.24 (d, J = 15.92 Hz, 2 H) 8.40 (s, 1 H) 9.23 (br. s.,1 H) 66

  2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran- 4-yl)propanamide SeeCmpd. 10 [M + H] calc'd for C₂₁H₂₄FN₄ O₄S₂ 479.56, found 479.5 ¹H NMR(400 MHz, MeOD) δ ppm 0.94- 1.00 (m, 2 H) 1.17- 1.32 (m, 5 H) 1.35- 1.43(m, 1 H) 1.58- 1.67 (m, 1 H) 2.08- 2.18 (m, 1 H) 2.48 (ddd, J = 14.46,10.42, 4.42 Hz, 1 H) 2.72 (tt, J = 7.96, 4.80 Hz, 1 H) 3.04-3.17 (m, 2H) 3.69-3.82 (m, 2 H) 5.66 (dd, J = 10.61, 5.05 Hz, 1 H) 6.99 (d, J =2.53 Hz, 1 H) 7.55 (dd, J = 8.34, 7.33 Hz, 1 H) 7.66 (d, J = 6.57 Hz, 1H) 7.97 (d, J = 8.59 Hz, 1 H) 8.38 (s, 1 H) 67

  N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-6-fluoro-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran- 4-yl)propanamide SeeCmpd. 10 [M + H] calc'd for C₂₁H₂₃ClF N₄O₄S₂ 514.01, found 514 ¹H NMR(400 MHz, MeOD) δ ppm 1.09 (m, 2 H) 1.32 (m, 5 H) 1.47 (m, 1 H) 1.70 (m,1 H) 2.23 (m, 1 H) 2.56 (m, 1 H) 2.86 (m, 1 H) 3.20 (m, 2 H) 3.85 (m, 2H) 5.71 (m, 1 H) 7.56 (m, 1 H) 7.87 (m, 1 H) 8.47 (s, 1 H) 68

  (R)-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 10 [M + H] calc'd for C₂₁H₂₄FN₄ O₄S₂ 479.56, found 479.5 69

  (S)-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamideSee Cmpd. 10 [M + H] calc'd for C₂₁H₂₄FN₄ O₄S₂ 479.56, found 479.5 70

  N-(5-chlorothiazol-2-yl)-2-(4-(cyclo-propylsulfonyl)-2H-indazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M + H] calc'd forC₂₁H₂₄ClN₄ O₄S₂ 496.01, found 496.1 ¹H NMR (400 MHz, MeOD) δ ppm 0.93-1.00 (m, 2 H) 1.16- 1.36 (m, 5 H) 1.39- 1.47 (m, 1 H) 1.64- 1.74 (m, 1H) 2.09- 2.21 (m, 1 H) 2.40 (ddd, J = 14.46, 10.17, 4.67 Hz, 1 H) 2.71-2.75 (m, 1 H) 3.11- 3.20 (m, 2 H) 3.70- 3.84 (m, 2 H) 5.63 (dd, J =10.36, 5.31 Hz, 1 H) 7.24 (s, 1 H) 7.41 (dd, J = 8.59, 7.07 Hz, 1 H)7.62 (d, J = 6.32 Hz, 1 H) 7.89 (d, J = 8.84 Hz, 1 H) 8.67 (d, J = 1.01Hz, 1 H) 71

  2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-((R)-3-oxocyclopentyl)-N-(pyrazin- 2-yl)propanamide See Cmpd. 11[M + H] calc'd for C₂₂H₂₄N₅ O₄S 454.2, found 454.0 see separated dias-tereomers for ¹H NMR 72

  2-(4-(cyclopropylsulfonyl)-6-methoxy-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 10 [M + H] calc'd for C₂₂H₂₆FN₄ O₅S₂ 509, found 509 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 8.52 (s, 1 H), 7.45 (d, J = 1.8 Hz, 1 H),7.00 (br. s., 1 H), 6.96 (s, 1 H), 5.30 (s, 1 H), 3.95 (s, 3 H),3.78-3.93 (m, 2 H), 3.13-3.30 (m, 2 H), 2.57-2.73 (m, 1 H), 2.50 (br.s., 1 H), 2.25 (d, J = 5.6 Hz, 1 H), 1.59 (d, J = 12.4 Hz, 1 H),1.44-1.55 (m, 2 H), 1.28-1.44 (m, 4 H), 1.01-1.16 ppm (m, 2 H) 73

  2-(4-(cyclopropylsulfonyl)-6-methoxy-2H-indazol-2-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 10 [M + H] calc'd for C₂₂H₂₆FN₄ O₅S₂ 509, found 509 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 8.37 (s, 1 H), 7.45 (d, J = 2.0 Hz, 1 H),7.27 (d, J = 2.0 Hz, 1 H), 7.02 (d, J = 2.8 Hz, 1 H), 5.25 (dd, J =10.0, 5.4 Hz, 1 H), 3.95 (s, 3 H), 3.73- 3.91 (m, 2 H), 3.20- 3.33 (m, 2H), 2.49- 2.58 (m, 1 H), 2.37- 2.48 (m, 1 H), 2.21- 2.32 (m, 1 H), 1.69(d, J = 12.1 Hz, 1 H), 1.51 (dd, J = 9.3, 2.0 Hz, 1 H), 1.28-1.45 (m, 5H), 0.99-1.08 ppm (m, 2 H) 74

  (S)-2-(4-(cyclopropylsulfonyl)-1H- indazol-1-yl)-3-((R)-3-oxocyclo-pentyl)-N-(pyrazin-2-yl) propanamide See Cmpd. 11 [M + H] calc'd forC₂₂H₂₄N₅ O₄S 454.2, found 454.0 ¹H NMR (400 MHz, MeOD) δ ppm 1.01- 1.14(m, 2 H) 1.16- 1.32 (m, 2 H) 1.62- 1.85 (m, 2 H) 2.00- 2.13 (m, 3 H)2.15- 2.29 (m, 2 H) 2.52 (ddd, J = 14.08, 7.14, 5.05 Hz, 1 H) 2.65-2.86(m, 2 H) 5.79 (dd, J = 10.11, 5.05 Hz, 1 H) 7.55- 7.72 (m, 1 H) 7.76 (d,J = 6.57 Hz, 1 H) 8.14 (d, J = 8.59 Hz, 1 H) 8.24-8.44 (m, 2 H) 8.51 (s,1 H) 9.29-9.37 (m, 1 H) 75

  (R)-2-(4-(cyclopropylsulfonyl)-1H- indazol-1-yl)-3-((R)-3-oxocyclo-pentyl)-N-(pyrazin-2-yl) propanamide See Cmpd. 11 [M + H] calc'd forC₂₂H₂₄N₅ O₄S 454.2, found 454.0 ¹H NMR (400 MHz, MeOD) δ ppm 0.92- 1.13(m, 2 H) 1.18- 1.37 (m, 2 H) 1.50- 1.68 (m, 1 H) 1.89- 2.13 (m, 4 H)2.14- 2.39 (m, 2 H) 2.44 (ddd, J = 13.96, 8.91, 4.93 Hz, 1 H) 2.70- 2.92(m, 2 H) 5.73 (dd, J = 10.61, 4.80 Hz, 1 H) 7.52-7.73 (m, 1 H) 7.75 (d,J = 6.82 Hz, 1 H) 8.13 (d, J = 8.59 Hz, 1 H) 8.35 (br. s., 2 H) 8.51 (s,1 H) 9.33 (br. s., 1 H) 76

  (S)-2-(4-(cyclopropylsulfonyl)-6-hydroxy-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M + H] calc'd forC₂₁H₂₄FN₄ O₅S₂ 495, found 495 ¹H NMR (DMSO-d₆, 400 MHz): δ = 12.70 (s, 1H), 10.48 (s, 1 H), 8.23 (s, 1 H), 7.33-7.36 (m, 2 H), 7.23 (d, J = 1.8Hz, 1 H), 5.62 (d, J = 4.3 Hz, 1 H), 3.71- 3.85 (m, 3 H), 3.06- 3.21 (m,2 H), 2.24- 2.41 (m, 1 H), 2.09- 2.24 (m, 1 H), 1.54- 1.63 (m, 1 H),1.48 (br. s., 1 H), 1.28 (br. s., 3 H), 1.16 (br. s., 2 H), 1.06 ppm(dd, J = 7.8, 2.0 Hz, 2 H) 77

  (R)-2-(4-(cyclopropylsulfonyl)-6-hydroxy-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M + H] calc'd forC₂₁H₂₄FN₄ O₅S₂ 495, found 495 ¹H NMR (DMSO-d₆, 400 MHz): δ = 12.70 (s, 1H), 10.48 (s, 1 H), 8.23 (s, 1 H), 7.33-7.36 (m, 2 H), 7.23 (d, J = 1.8Hz, 1 H), 5.62 (d, J = 4.3 Hz, 1 H), 3.71- 3.85 (m, 3 H), 3.06- 3.21 (m,2 H), 2.24- 2.41 (m, 1 H), 2.09- 2.24 (m, 1 H), 1.54- 1.63 (m, 1 H),1.48 (br. s., 1 H), 1.28 (br. s., 3 H), 1.16 (br. s., 2 H), 1.06 ppm(dd, J = 7.8, 2.0 Hz, 2 H) 78

  (R)-2-(6-chloro-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-((R)-3-oxocyclopentyl)propanamide See Cmpd. 11 [M + H] calc'd forC₂₁H₂₁ClF N₄O₄S₂ 511.1, found 511.3 ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.07-1.31 (m, 2 H) 1.34-1.57 (m, 2 H) 1.57-1.84 (m, 3 H) 1.93-2.21 (m, 3H) 2.32 (dd, J = 18.32, 8.21 Hz, 1 H) 2.47-2.70 (m, 2 H) 2.97-3.20 (m, 1H) 5.33 (dd, J = 9.98, 5.18 Hz, 1 H) 6.93- 7.13 (m, 1 H) 7.71- 7.91 (m,2 H) 8.49- 8.69 (m, 1 H) 79

  (S)-2-(6-chloro-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-((R)-3-oxocyclopentyl)propanamide See Cmpd. 11 [M + H] calc'd for C₂₁H₂₁ClFN₄O₄S₂ 511.1, found 511.3 ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07-1.31(m, 2 H) 1.39-1.69 (m, 4 H) 1.81-1.92 (m, 1 H) 1.93-2.14 (m, 2 H)2.18-2.38 (m, 2 H) 2.46 (ddd, J = 14.02, 8.84, 5.18 Hz, 1 H) 2.53-2.79(m, 2 H) 5.27 (dd, J = 10.48, 4.93 Hz, 1 H) 7.03 (d, J = 3.03 Hz, 1 H)7.71- 7.93 (m, 2 H) 8.63 (s, 1 H) 80

  2-(4-(cyclopropylsulfonyl)-5-methoxy-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 15 [M + H] calc'd forC₂₂H₂₆FN₄ O₅S₂ 509, found 509 ¹H NMR (CHLOROFORM-d, 400 MHz): δ = 8.74(s, 1 H), 7.67 (d, J = 9.1 Hz, 1 H), 7.33 (d, J = 9.3 Hz, 1 H), 7.02 (d,J = 2.8 Hz, 1 H), 5.37 (dd, J = 10.6, 4.8 Hz, 1 H), 4.08 (s, 3 H), 3.82-3.95 (m, 2 H), 3.05- 3.29 (m, 3 H), 2.49 (ddd, J = 14.2, 10.5, 5.1 Hz, 1H), 2.23 (ddd, J = 14.0, 8.8, 4.8 Hz, 1 H), 1.53- 1.66 (m, 1 H), 1.42-1.49 (m, 2 H), 1.27- 1.42 (m, 3 H), 1.21 (dd, J = 7.5, 3.9 Hz, 1 H),1.02 ppm (dddd, J = 16.8, 8.1, 6.5, 4.9 Hz, 2 H) 81

  (R)-2-(4-(cyclopropylsulfonyl)-5-methoxy-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 15 [M + H] calc'd forC₂₂H₂₆FN₄ O₅S₂ 509, found 509 ¹H NMR (CHLOROFORM-d, 400 MHz): δ = 8.74(s, 1 H), 7.67 (d, J = 9.1 Hz, 1 H), 7.33 (d, J = 9.3 Hz, 1 H), 7.02 (d,J = 2.8 Hz, 1 H), 5.37 (dd, J = 10.6, 4.8 Hz, 1 H), 4.08 (s, 3 H), 3.82-3.95 (m, 2 H), 3.05- 3.29 (m, 3 H), 2.49 (ddd, J = 14.2, 10.5, 5.1 Hz, 1H), 2.23 (ddd, J = 14.0, 8.8, 4.8 Hz, 1 H), 1.53- 1.66 (m, 1 H), 1.42-1.49 (m, 2 H), 1.27- 1.42 (m, 3 H), 1.21 (dd, J = 7.5, 3.9 Hz, 1 H),1.02 ppm (dddd, J = 16.8, 8.1, 6.5, 4.9 Hz, 2 H) 82

  (S)-2-(4-(cyclopropylsulfonyl)-5-methoxy-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 15 [M + H] calc'd forC₂₂H₂₆FN₄ O₅S₂ 509, found 509 ¹H NMR (CHLOROFORM-d, 400 MHz): δ = 8.74(s, 1 H), 7.67 (d, J = 9.1 Hz, 1 H), 7.33 (d, J = 9.3 Hz, 1 H), 7.02 (d,J = 2.8 Hz, 1 H), 5.37 (dd, J = 10.6, 4.8 Hz, 1 H), 4.08 (s, 3 H),3.82-3.95 (m, 2 H), 3.05- 3.29 (m, 3 H), 2.49 (ddd, J = 14.2, 10.5, 5.1Hz, 1 H), 2.23 (ddd, J = 14.0, 8.8, 4.8 Hz, 1 H), 1.53- 1.66 (m, 1 H),1.42- 1.49 (m, 2 H), 1.27- 1.42 (m, 3 H), 1.21 (dd, J = 7.5, 3.9 Hz, 1H), 1.02 ppm (dddd, J = 16.8, 8.1, 6.5, 4.9 Hz, 2 H) 83

  2-(4-(cyclopropylsulfonyl)-6-methoxy-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M + H] calc'd forC₂₃H₃₀N₅ O₅S 488, found 488 ¹H NMR (CHLOROFORM-d, 400 MHz): δ = 10.28(s, 1 H), 8.45 (s, 1 H), 7.42 (d, J = 1.8 Hz, 1 H), 7.33 (d, J = 2.3 Hz,1 H), 7.12-7.18 (m, 1 H), 6.77 (d, J = 2.5 Hz, 1 H), 5.40 (dd, J = 10.1,5.1 Hz, 1 H), 3.93 (s, 3 H), 3.90-4.04 (m, 2 H), 3.85 (s, 3 H),3.21-3.40 (m, 2 H), 2.48-2.66 (m, 2 H), 2.22-2.34 (m, 1 H), 1.68 (d, J =12.4 Hz, 1 H), 1.51-1.61 (m, 1 H), 1.28-1.50 (m, 5 H), 0.97-1.12 ppm (m,2 H) 84

  (S)-2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 13 [M + H] calc'd forC₂₀H₂₃FN₅ O₄S₂ 480, found 480 ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.09-1.19 (m, 2 H) 1.21-1.29 (m, 1 H) 1.31-1.55 (m, 5 H) 1.59-1.72 (m, 1H) 2.33 (ddd, J = 14.15, 8.34, 5.31 Hz, 1 H) 2.42-2.56 (m, 1 H) 2.64(tt, J = 7.96, 4.80 Hz, 1 H) 3.22 (m, J = 17.91, 11.64, 11.64, 2.27 Hz,2 H) 3.90 (ddd, J = 13.45, 11.43, 2.65 Hz, 2 H) 5.61 (dd, J = 10.23,5.43 Hz, 1 H) 7.09 (d, J = 2.78 Hz, 1 H) 8.65 (s, 1 H) 8.87 (s, 1 H)9.34 (s, 1 H) 9.99 (br. s., 1 H) 85

  (R)-2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 13 [M + H] calc'd forC₂₀H₂₃FN₅ O₄S₂ 480, found 480 86

  N-(3-cyanopyridin-2-yl)-2-(4-(cyclopropyl-sulfonyl)-1H-indazol-1-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamide SeeCmpd. 10 [M + H] calc'd for C₂₄H₂₆N₅ O₄S 480.3, found 480.5 ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 0.89-1.05 (m, 2 H) 1.18-1.45 (m, 5 H) 1.49 (d,J = 9.60 Hz, 1 H) 1.53-1.65 (m, 1 H) 2.15-2.36 (m, 3 H) 2.36-2.63 (m, 2H) 3.07-3.28 (m, 2 H) 3.83 (t, J = 10.74 Hz, 2 H) 5.44 (dd, J = 9.98,5.18 Hz, 1 H) 7.55 (dd, J = 8.72, 7.20 Hz, 1 H) 7.73 (d, J = 7.58 Hz, 2H) 7.91 (d, J = 7.83 Hz, 1 H) 8.62 (s, 1 H), 9.50 (s, 1H) 87

  2-(4-(cyclopropylsulfonyl)-5-(difluoromethoxy)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 12 [M + H] calc'd forC₂₂H₂₄ F₃N₄O₅S₂ 545, found 545 ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.02-1.13 (m, 2 H) 1.34-1.49 (m, 4 H) 1.50-1.61 (m, 1 H) 1.65-1.76 (m, 1H) 2.24-2.35 (m, 1 H) 2.47-2.60 (m, 1 H) 2.66-2.77 (m, 2 H) 3.20-3.36(m, 2 H) 3.89-3.99 (m, 2 H) 5.46 (dd, J = 10.86, 4.80 Hz, 1 H) 6.93 (s,1 H) 7.07-7.13 (m, 1 H) 7.29-7.60 (m, 1 H) 7.58-7.67 (m, 1 H) 8.27 (s, 1H) 88

  2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(3,5-difluoropyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M + H] calc'd forC₂₃H₂₅ F2N₄O₄S 491.5, found 491.6 ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.94-1.13 (m, 2 H) 1.13-1.37 (m, 4 H) 1.47-1.59 (m, 1 H) 1.66 (d, J =10.11 Hz, 1 H) 2.25 (d, J = 7.83 Hz, 1 H) 2.34-2.47 (m, 1 H) 2.92-3.22(m, 4 H) 3.71-3.86 (m, 2 H) 5.82 (dd, J = 9.73, 5.43 Hz, 1 H) 7.59- 7.79(m, 2 H) 8.02 (ddd, J = 9.79, 8.40, 2.53 Hz, 1 H) 8.21 (d, J = 8.34 Hz,1 H) 8.35 (d, J = 2.53 Hz, 1 H) 8.39-8.51 (m, 1 H) 10.73 (s, 1 H) 89

  (S)-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamide See Cmpd. 10[M + H] calc'd for C₂₂H₂₆N₅ O₄S 456.53, found 456.5 90

  (R)-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H-pyran- 4-yl)propanamide See Cmpd.10 [M + H] calc'd for C₂₂H₂₆N₅ O₄S 456.53, found 456.5 91

  2-(4-(cyclopropylsulfonyl)-5-methoxy-1H-indazol-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 15 [M + H] calc'd for C₂₃H₂₈N₅ O₅S 486, found 486 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 9.49 (s, 1 H), 9.20 (s, 1 H), 8.79 (s, 1H), 8.32 (d, J = 1.5 Hz, 1 H), 8.36 (d, J = 2.5 Hz, 1 H), 7.71 (d, J =9.3 Hz, 1 H), 7.35 (d, J = 9.3 Hz, 1 H), 5.34 (dd, J = 10.5, 4.9 Hz, 1H), 4.08 (s, 3 H), 3.85-3.99 (m, 2 H), 3.07-3.32 (m, 3 H), 2.54 (d, J =3.5 Hz, 1 H), 2.28 (d, J = 5.3 Hz, 1 H), 1.60 (br. s., 1 H), 1.26- 1.48(m, 6 H), 0.92- 1.12 ppm (m, 2 H) 92

  2-(4-(cyclopropylsulfonyl)-6-methoxy-1H-indazol-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H-pyran- 4-yl)propanamide SeeCmpd. 10 [M + H] calc'd for C₂₃H₂₈N₅ O₅S 486, found 486 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 9.50 (s, 1 H), 9.22 (s, 1 H), 8.55 (s, 1H), 8.33- 8.41 (m, 1 H), 8.28 (s, 1 H), 7.44 (d, J = 2.0 Hz, 1 H), 7.03(d, J = 1.3 Hz, 1 H), 5.31 (dd, J = 10.5, 4.9 Hz, 1 H), 3.95 (s, 4 H),3.87-3.97 (m, 1 H), 3.25-3.32 (m, 1 H), 3.21 (td, J = 11.7, 2.5 Hz, 1H), 2.51-2.65 (m, 2 H), 2.25-2.35 (m, 1 H), 1.52-1.66 (m, 2 H),1.31-1.50 (m, 5 H), 1.02-1.13 ppm (m, 2 H) 93

  (R)-2-(4-(cyclopropylsulfonyl)-5-methoxy-1H-indazol-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 15 [M + H] calc'd for C₂₃H₂₈N₅ O₅S 486, found 486 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 9.49 (s, 1 H), 9.20 (s, 1 H), 8.79 (s, 1H), 8.32 (d, J = 1.5 Hz, 1 H), 8.36 (d, J = 2.5 Hz, 1 H), 7.71 (d, J =9.3 Hz, 1 H), 7.35 (d, J = 9.3 Hz, 1 H), 5.34 (dd, J = 10.5, 4.9 Hz, 1H), 4.08 (s, 3 H), 3.85-3.99 (m, 2 H), 3.07-3.32 (m, 3 H), 2.54 (d, J =3.5 Hz, 1 H), 2.28 (d, J = 5.3 Hz, 1 H), 1.60 (br. s., 1 H), 1.26-1.48(m, 6 H), 0.92- 1.12 ppm (m, 2 H) 94

  (S)-2-(4-(cyclopropylsulfonyl)-5-methoxy-1H-indazol-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 15 [M + H] calc'd for C₂₃H₂₈N₅ O₅S 486, found 486 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 9.49 (s, 1 H), 9.20 (s, 1 H), 8.79 (s, 1H), 8.32 (d, J = 1.5 Hz, 1 H), 8.36 (d, J = 2.5 Hz, 1 H), 7.71 (d, J =9.3 Hz, 1 H), 7.35 (d, J = 9.3 Hz, 1 H), 5.34 (dd, J = 10.5, 4.9 Hz, 1H), 4.08 (s, 3 H), 3.85- 3.99 (m, 2 H), 3.07- 3.32 (m, 3 H), 2.54 (d, J= 3.5 Hz, 1 H), 2.28 (d, J = 5.3 Hz, 1 H), 1.60 (br. s., 1 H), 1.26-1.48(m, 6 H), 0.92-1.12 ppm (m, 2 H) 95

  2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 16 [M + H] calc'd forC₂₁H₂₇N₆ O₄S 459, found 459 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm1.08-1.18 (m, 2 H) 1.28-1.44 (m, 5 H) 1.54 (d, J = 9.35 Hz, 1 H) 1.74(dd, J = 10.11, 1.77 Hz, 1 H) 2.17-2.27 (m, 1 H) 2.67 (ddd, J = 14.21,10.93, 3.66 Hz, 1 H) 2.89 (tt, J = 7.86, 4.77 Hz, 1 H) 3.10-3.28 (m, 2H) 3.76 (s, 3 H) 3.85 (dd, J = 10.74, 4.93 Hz, 2 H) 5.99 (dd, J = 10.99,4.67 Hz, 1 H) 6.42 (d, J = 2.53 Hz, 1 H) 7.42 (d, J = 2.27 Hz, 1 H) 7.69(d, J = 4.80 Hz, 1 H) 8.51 (s, 1 H) 8.81 (d, 1 H) 96

  2-(6-amino-4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide See Cmpd. 16 [M + H] calc'dfor C₂₁H₂₆N₇ O₄S 472, found 472 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm0.99-1.06 (m, 2 H) 1.29-1.44 (m, 5 H) 1.52 (d, J = 9.35 Hz, 1 H)1.71-1.79 (m, 1 H) 2.13-2.22 (m, 1 H) 2.56-2.66 (m, 1 H) 2.90 (tt, J =7.96, 4.80 Hz, 1 H) 3.12- 3.29 (m, 2 H) 3.86 (t, J = 10.74 Hz, 2 H) 5.90(dd, J = 10.99, 4.42 Hz, 1 H) 8.17 (s, 1 H) 8.27-8.37 (m, 3 H) 9.31 (s,1 H) 97

  2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 16 & 95 [M + H] calc'dfor C₂₁H₂₅N₆ O₄S 457, found 457 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm1.09-1.20 (m, 2 H) 1.32-1.47 (m, 5 H) 1.56 (dd, J = 9.47, 1.89 Hz, 1 H)1.76 (dd, J = 9.73, 1.89 Hz, 1 H) 2.20-2.29 (m, 1 H) 2.73 (ddd, J =14.15, 11.12, 3.54 Hz, 1 H) 2.91 (tt, J = 7.96, 4.80 Hz, 1 H) 3.12- 3.29(m, 2 H) 3.81- 3.91 (m, 2 H) 6.10 (dd, J = 11.12, 4.29 Hz, 1 H) 7.71 (d,J = 4.55 Hz, 1 H) 8.31 (d, J = 2.53 Hz, 1 H) 8.36 (dd, J = 2.53, 1.52Hz, 1 H) 8.53 (s, 1 H) 8.83 (d, J = 4.80 Hz, 1 H) 9.29 (s, 1 H) 98

  (S)-2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide See Cmpd. 16 & 95 [M + H]calc'd for C₂₁H₂₇N₆ O₄S 459, found 459 ¹H NMR (400 MHz, METHANOL-d₄) δppm 1.08-1.18 (m, 2 H) 1.28-1.44 (m, 5 H) 1.54 (d, J = 9.35 Hz, 1 H)1.74 (dd, J = 10.11, 1.77 Hz, 1 H) 2.17- 2.27 (m, 1 H) 2.67 (ddd, J =14.21, 10.93, 3.66 Hz, 1 H) 2.89 (tt, J = 7.86, 4.77 Hz, 1 H) 3.10-3.28(m, 2 H) 3.76 (s, 3 H) 3.85 (dd, J = 10.74, 4.93 Hz, 2 H) 5.99 (dd, J =10.99, 4.67 Hz, 1 H) 6.42 (d, J = 2.53 Hz, 1 H) 7.42 (d, J = 2.27 Hz, 1H) 7.69 (d, J = 4.80 Hz, 1 H) 8.51 (s, 1 H) 8.81 (d, 1 H) 99

  (R)-2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide See Cmpd. 16 & 95 [M + H]calc'd for C₂₁H₂₇N₆ O₄S 459, found 459 ¹H NMR (400 MHz, METHANOL-d₄) δppm 1.08-1.18 (m, 2 H) 1.28-1.44 (m, 5 H) 1.54 (d, J = 9.35 Hz, 1 H)1.74 (dd, J = 10.11, 1.77 Hz, 1 H) 2.17- 2.27 (m, 1 H) 2.67 (ddd, J =14.21, 10.93, 3.66 Hz, 1 H) 2.89 (tt, J = 7.86, 4.77 Hz, 1 H) 3.10-3.28(m, 2 H) 3.76 (s, 3 H) 3.85 (dd, J = 10.74, 4.93 Hz, 2 H) 5.99 (dd, J =10.99, 4.67 Hz, 1 H) 6.42 (d, J = 2.53 Hz, 1 H) 7.42 (d, J = 2.27 Hz, 1H) 7.69 (d, J = 4.80 Hz, 1 H) 8.51 (s, 1 H) 8.81 (d, 1 H) 100

  2-(6-cyano-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamideSee Cmpd. 19 [M + H] calc'd for C₂₃H₂₅N₆ O₄S 481, found 481 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 9.55 (br. s., 1 H), 9.40 (br. s., 1 H),8.74 (s, 1 H), 8.45 (br. s., 1 H), 8.37 (br. s., 1 H), 8.22 (s, 1 H),7.99 (s, 1 H), 5.52 (dd, J = 9.9, 5.8 Hz, 1 H), 3.90-4.09 (m, 2 H),3.19-3.41 (m, 2 H), 2.48-2.68 (m, 2 H), 2.39 (dd, J = 13.8, 7.7 Hz, 1H), 1.68 (d, J = 12.1 Hz, 1 H), 1.57-1.64 (m, 1 H), 1.34-1.54 (m, 5 H),1.09-1.19 ppm (m, 2 H) 101

  2-(6-chloro-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M + H] calc'd for C₂₂H₂₇Cl N₅O₄S492, found 492 ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.57 (s, 2H), 7.67- 7.82(m, 2H), 7.23 (d, J = 2.53 Hz, 1H), 6.62 (s, 1H), 5.28 (dd, J = 5.18,10.23 Hz, 1H), 3.84-3.98 (m, 2H), 3.76 (s, 3H), 3.10-3.32 (m, 2H),2.56-2.67 (m, 1H), 2.43-2.56 (m, 1H), 2.23 -2.36 (m, 1H), 1.57-1.63 (m,2H), 1.30-1.56 (m, 5H), 1.02-1.16 (m, 2H) 102

  2-(6-chloro-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamideSee Cmpd. 10 [M + H] calc'd for C₂₂H₂₅Cl N₅O₄S 490, found 490 ¹H NMR(400 MHz, CHLOROFORM-d) δ 9.47-9.50 (m, 1H), 8.93 (s, 1H), 8.64 (s, 1H),8.36 (d, J = 2.53 Hz, 1H), 8.23 (dd, J = 1.52, 2.53 Hz, 1H), 7.70-7.83(m, 2H), 5.34 (dd, J = 5.31, 10.36 Hz, 1H), 3.80-3.97 (m, 2H), 3.14-3.35(m, 2H), 2.47-2.67 (m,2H), 2.27-2.38 (m, 1H), 1.53-1.65 (m, 2H),1.31-1.52 (m,5H), 1.04-1.16 (m, 2H) 103

  2-(4-(cyclopropylsulfonyl)-6-fluoro-1H-indazol-1-yl)-N-(pyrazin-2-yl)-3- (tetrahydro-2H-pyran-4-yl)propanamideSee Cmpd. 10 [M + H] calc'd for C₂₂H₂₅FN₅ O₄S 474, found 474 ¹H NMR (400MHz, METHANOL-d₄) δ ppm 1.05-1.13 (m, 2 H) 1.28-1.44 (m, 5 H) 1.52 (dd,J = 9.47, 1.89 Hz, 1 H) 1.68-1.77 (m, 1 H) 2.19-2.28 (m, 1 H) 2.55-2.65(m, 1 H) 2.81-2.90 (m, 1 H) 3.16-3.29 (m, 2 H) 3.80-3.92 (m, 2 H) 5.73(dd, J = 10.61, 5.05 Hz, 1 H) 7.57 (dd, J = 8.34, 2.02 Hz, 1 H)7.89-7.94 (m, 1 H) 8.32 (d, J = 2.53 Hz, 1 H) 8.34-8.39 (m, 1 H) 8.48(s, 1 H) 9.32 (d, 1 H) 104

  2-(4-(cyclopropylsulfonyl)-6-fluoro-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M + H] calc'd forC₂₂H₂₇FN₅ O₄S 476, found 476 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm1.05-1.13 (m, 2 H) 1.27-1.43 (m, 5 H) 1.49-1.57 (m, 1 H) 1.72 (dd, J =10.23, 1.89 Hz, 1 H) 2.18-2.27 (m, 1 H) 2.50-2.59 (m, 1 H) 2.81-2.89 (m,1 H) 3.16-3.29 (m, 2 H) 3.77 (s, 3 H) 3.81-3.91 (m, 2 H) 5.60 (dd, J =10.36, 5.31 Hz, 1 H) 6.45 (d, J = 2.27 Hz, 1 H) 7.43 (d, J = 2.27 Hz, 1H) 7.56 (dd, J = 8.34, 2.02 Hz, 1 H) 7.90 (dd, J = 9.09, 1.01 Hz, 1 H)8.46 (s, 1 H) 105

  (S)-2-(6-cyano-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Ex Cmpd. 19 [M + H] calc'dfor C₂₃H₂₇N₆ O₄S 483, found 483 ¹H NMR (CHLOROFORM-d, 400 MHz): δ = 8.68(s, 1 H), 8.45 (s, 1 H), 8.17 (s, 1 H), 7.95 (d, J = 1.0 Hz, 1 H), 7.24(d, J = 2.3 Hz, 1 H), 6.62 (d, J = 2.3 Hz, 1 H), 5.39 (dd, J = 9.9, 5.8Hz, 1 H), 3.91 (t, J = 11.7 Hz, 2 H), 3.77 (s, 3 H), 3.15-3.32 (m, 2 H),2.56- 2.66 (m, 1 H), 2.49 (s, 1 H), 2.36 (d, J = 5.8 Hz, 1 H), 1.62 (m,1 H), 1.31-1.50 (m, 6 H), 1.08-1.19 ppm (m, 2 H) 106

  (R)-2-(6-cyano-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 19 [M + H] calc'd forC₂₃H₂₇N₆ O₄S 483, found 483 ¹H NMR (CHLOROFORM-d, 400 MHz): δ = 8.68 (s,1 H), 8.45 (s, 1 H), 8.17 (s, 1 H), 7.95 (d, J = 1.0 Hz, 1 H), 7.24 (d,J = 2.3 Hz, 1 H), 6.62 (d, J = 2.3 Hz, 1 H), 5.39 (dd, J = 9.9, 5.8 Hz,1 H), 3.91 (t, J = 11.7 Hz, 2 H), 3.77 (s, 3 H), 3.15-3.32 (m, 2 H),2.56-2.66 (m, 1 H), 2.49 (s, 1 H), 2.36 (d, J = 5.8 Hz, 1 H), 1.62 (m, 1H), 1.31- 1.50 (m, 6 H), 1.08- 1.19 ppm (m, 2 H) 107

  (S)-6-(2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamido)nicotinamide See Cmpd. 14 [M + H] calc'd forC₂₄H₂₈N₅ O₅S 498.5, found 498.5 108

  (R)-6-(2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamido)nicotinamide See Cmpd. 14 [M + H] calc'd forC₂₄H₂₈N₅ O₅S 498.5, found 498.5 109

  (S)-2-(4-(cyclopropylsulfonyl)-5-methoxy-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 15 [M + H] calc'd for C₂₃H₂₉N₅ O₅S 488,found 488 ¹H NMR (CHLOROFORM-d, 400 MHz): δ = 8.72 (s, 1 H), 8.64 (s, 1H), 7.67 (d, J = 9.3 Hz, 1 H), 7.30 (d, J = 9.1 Hz, 1 H), 7.22 (d, J =2.5 Hz, 1 H), 6.61 (d, J = 2.3 Hz, 1 H), 5.27 (dd, J = 10.6, 4.8 Hz, 1H), 4.07 (s, 3 H), 3.82-3.92 (m, 2 H), 3.75 (s, 3 H), 3.09-3.29 (m, 3H), 2.44-2.56 (m, 1 H), 2.28 (d, J = 5.1 Hz, 1 H), 1.42-1.52 (m, 2 H),1.29-1.40 (m, 3H), 1.21 (d, J = 6.1 Hz, 2 H), 0.95- 1.09 ppm (m, 2 H)110

  (R)-2-(4-(cyclopropylsulfonyl)-5-methoxy-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 15 [M + H]calc'd for C₂₃H₂₉N₅ O₅S 488, found 488 ¹H NMR (CHLOROFORM-d, 400 MHz): δ= 8.72 (s, 1 H), 8.64 (s, 1 H), 7.67 (d, J = 9.3 Hz, 1 H), 7.30 (d, J =9.1 Hz, 1 H), 7.22 (d, J = 2.5 Hz, 1 H), 6.61 (d, J = 2.3 Hz, 1 H), 5.27(dd, J = 10.6, 4.8 Hz, 1 H), 4.07 (s, 3 H), 3.82-3.92 (m, 2 H), 3.75 (s,3 H), 3.09-3.29 (m, 3 H), 2.44-2.56 (m, 1 H), 2.28 (d, J = 5.1 Hz, 1 H),1.42-1.52 (m, 2 H), 1.29-1.40 (m, 3 H), 1.21 (d, J = 6.1 Hz, 2 H),0.95-1.09 ppm (m, 2 H) 111

  (R)-2-(6-amino-4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 16 [M + H] calc'd forC₂₀H₂₄FN₆ O₄S₂ 495.5, found 495.5 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm0.99-1.07 (m, 9 H) 1.29-1.42 (m, 22 H) 1.47- 1.54 (m, 4 H) 1.71- 1.78(m, 4 H) 2.09- 2.19 (m, 4 H) 2.52- 2.63 (m, 5 H) 2.90 (tt, J = 8.08,4.80 Hz, 5 H) 3.12-3.28 (m, 9 H) 3.80-3.90 (m, 9 H) 5.86 (dd, J = 10.99,4.42 Hz, 5 H) 7.08 (d, J = 2.53 Hz, 4 H) 8.15 (s, 4 H) 8.32 (s, 4 H).112

  (S)-2-(6-amino-4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 16 [M + H] calc'd forC₂₀H₂₄FN₆ O₄S₂ 495.5, found 495.5 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm0.99-1.07 (m, 9H) 1.29-1.42 (m, 22 H) 1.47-1.54 (m, 4 H) 1.71-1.78 (m, 4H) 2.09-2.19 (m, 4 H) 2.52-2.63 (m, 5 H) 2.90 (tt, J = 8.08, 4.80 Hz, 5H) 3.12-3.28 (m, 9 H) 3.80-3.90 (m, 9 H) 5.86 (dd, J = 10.99, 4.42 Hz, 5H) 7.08 (d, J = 2.53 Hz, 4 H) 8.15 (s, 4 H) 8.32 (s, 4 H). 113

  (S)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropyl-sulfonyl)-1H-indazol-1-yl)-3-((R)-3- oxocyclopentyl)propanamide SeeCmpd. 11 [M + H] calc'd for C₂₁H₂₂Cl N₄O₄S₂ 493.1, found 493.2 114

  (R)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropyl-sulfonyl)-1H-indazol-1-yl)-3-((R)-3- oxocyclopentyl)propanamide SeeCmpd. 11 [M + H] calc'd for C₂₁H₂₂Cl N₄O₄S₂ 493.1, found 493.2 ¹H NMR(400 MHz, METHANOL-d₄) δ ppm 0.94-1.13 (m, 2 H) 1.18-1.38 (m, 3 H)1.55-1.74 (m, 3 H) 1.75-2.04 (m, 3 H) 2.21-2.41 (m, 1 H) 2.49-2.72 (m, 1H) 2.73-2.89 (m, 1 H) 5.56-5.80 (m, 1 H) 7.30 (s, 1 H) 7.64 (dd, J =8.59, 7.33 Hz, 1 H) 7.75 (d, J = 7.07 Hz, 1 H) 8.07 (dd, J = 8.59, 3.03Hz, 1 H) 8.48 (s, 1 H) 115

  2-(4-(cyclopropylsulfonyl)-6-fluoro-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide See Cmpd.10 [M + H] calc'd for C₂₁H₂₂F₂ N₄O₄S₃ 498, found 498 ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.05-1.13 (m, 2 H) 1.25-1.37 (m, 5H) 1.45-1.53 (m, 1H) 1.67-1.75 (m, 1 H) 2.17-2.27 (m, 1 H) 2.55 (ddd, J = 14.46, 10.42,4.42 Hz, 1 H) 2.85 (tt, J = 7.96, 4.80 Hz, 1 H) 3.15-3.28 (m, 2 H)3.79-3.91 (m, 2 H) 5.69 (dd, J = 10.61, 5.05 Hz, 1 H) 7.09 (d, J = 2.78Hz, 1 H) 7.57 (dd, J = 8.34, 2.02 Hz, 1 H) 7.87 (dd, J = 9.09, 1.01 Hz,1 H) 8.46 (s, 1 H) 116

  2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(6-methylpyridazin-3-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamide See Cmpd.10 [M + H] calc'd for C₂₃H₂₇N₅ O₄S 471, found 471 ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.02-1.09 (m, 2 H) 1.25- 1.44 (m, 5 H) 1.49 (dd, J =9.35, 1.77 Hz, 1 H) 1.72 (d, J = 12.13 Hz, 1 H) 2.21-2.30 (m, 1 H) 2.62(ddd, J = 14.15, 10.61, 3.79 Hz, 1 H) 2.72 (s, 3 H) 2.80 (tt, J = 7.89,4.74 Hz, 1 H) 3.13-3.27 (m, 2 H) 3.79-3.91 (m, 2 H) 5.84 (dd, J = 10.61,4.80 Hz, 1 H) 7.64 (dd, J = 8.46, 7.20 Hz, 1 H) 7.75 (d, J = 6.57 Hz, 1H) 7.99 (d, J = 9.35 Hz, 1 H) 8.10 (d, J = 8.59 Hz, 1 H) 8.48 (s, 1 H)8.71 (d, 1 H) 117

  6-(2-(4-(cyclopropylsulfonyl)-6-fluoro-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamido)nicotinamide See Cmpd. 10 [M + H]calc'd for C₂₄H₂₆FN₅ O₅S 517, found 517 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.04-1.13 (m, 2 H) 1.17-1.38 (m, 5 H) 1.48-1.66 (m, 2 H) 2.19-2.29 (m, 1H) 2.40-2.48 (m, 1 H) 3.03-3.19 (m, 3 H) 3.72-3.84 (m, 2 H) 5.81 (dd, J= 9.73, 5.43 Hz, 1 H) 7.48 (s, 1 H) 7.60 (dd, J = 8.34, 2.02 Hz, 1 H)8.05 (s, 1 H) 8.18- 8.22 (m, 1 H) 8.45 (s, 1 H) 8.83 (d, J = 1.77 Hz, 1H) 11.26 (br. s., 1 H) 118

  (R)-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran- 4-yl)propanamide SeeCmpd. 10 [M + H] calc'd for C₂₂H₂₇N₅ O₄S 459, found 459 ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.02-1.09 (m, 2 H) 1.25-1.42 (m, 5 H) 1.53 (dd, J =9.60, 1.77 Hz, 1 H) 1.72 (dd, J = 9.98, 1.89 Hz, 1 H) 2.18- 2.28 (m, 1H) 2.54- 2.63 (m, 1 H) 2.81 (s, 1 H) 3.15-3.28 (m, 2 H) 3.76 (s, 3 H)3.81-3.90 (m, 2 H) 5.67 (dd, J = 10.36, 5.31 Hz, 1 H) 6.45 (d, J = 2.27Hz, 1 H) 7.43 (d, J = 2.27 Hz, 1 H) 7.63 (dd, J = 8.34, 7.33 Hz, 1 H)7.75 (d, J = 6.57 Hz, 1 H) 8.09 (d, J = 8.34 Hz, 1 H) 8.48 (s, 1 H) 119

  (S)-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide SeeCmpd. 10 [M + H] calc'd for C₂₂H₂₇N₅ O₄S 459, found 459 ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.02-1.09 (m, 2 H) 1.25-1.42 (m, 5 H) 1.53 (dd, J =9.60, 1.77 Hz, 1 H) 1.72 (dd, J = 9.98, 1.89 Hz, 1 H) 2.18-2.28 (m, 1 H)2.54-2.63 (m, 1 H) 2.81 (s, 1 H) 3.15- 3.28 (m, 2 H) 3.76 (s, 3 H)3.81-3.90 (m, 2 H) 5.67 (dd, J = 10.36, 5.31 Hz, 1 H) 6.45 (d, J = 2.27Hz, 1 H) 7.43 (d, J = 2.27 Hz, 1 H) 7.63 (dd, J = 8.34, 7.33 Hz, 1 H)7.75 (d, J = 6.57 Hz, 1 H) 8.09 (d, J = 8.34 Hz, 1 H) 8.48 (s, 1 H) 120

  2-(6-cyano-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamide SeeCmpd. 10 [M + H] calc'd for C₂₂H₂₂FN₅ O₄S₂ 505, found 505 ¹H NMR (400MHz, METHANOL-d₄) δ ppm 1.07-1.14 (m, 2 H) 1.27-1.45 (m, 5 H) 1.46-1.53(m, 1 H) 1.68-1.76 (m, 1 H) 2.23-2.32 (m, 1 H) 2.60 (ddd, J = 14.46,10.42, 4.42 Hz, 1 H) 2.89 (tt, J = 7.96, 4.80 Hz, 1 H) 3.16-3.28 (m, 2H) 3.80-3.91 (m, 2 H) 5.83 (dd, J = 10.61, 5.05 Hz, 1 H) 7.10 (d, J =2.78 Hz, 1 H) 7.99 (d, J = 1.26 Hz, 1 H) 8.59 (s, 1 H) 8.64 (s, 1 H) 121

  2-(6-chloro-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 10 [M + H] calc'd for C₂₁H₂₃ClF N₄O₄S₂ 514.0, found 514.0 ¹HNMR (400 MHz, METHANOL-d₄) δ 8.55 (s, 1H), 8.34 (s, 1H), 7.92 (s, 1H),7.00 (d, J = 2.78 Hz, 1H), 5.69 (dd, J = 5.43, 10.23 Hz, 1H), 3.82-3.92(m, 2H), 3.16-3.29 (m, 2H), 2.53-2.71 (m, 2H), 2.16-2.28 (m, 1H), 1.67(d, J = 12.13 Hz, 1H), 1.48-1.58 (m, 1H), 1.28-1.46 (m, 5H), 1.04-1.16(m, 2H) 122

  2-(4-(cyclopropylsulfonyl)-6-methyl-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamide SeeCmpd. 10 [M + H] calc'd for C₂₂H₂₆FN₄ O₄S₂ 493.5, found 493.5 ¹H NMR(400 MHz, METHANOL-d₄) δ 8.45 (s, 1H), 8.27 (s, 1H), 7.71 (s, 1H), 7.09(d, J = 2.53 Hz, 1H), 5.68 (dd, J = 5.05, 10.61 Hz, 1H), 3.79-3.91 (m,2H), 3.66 (s, 1H), 3.14- 3.27 (m, 2H), 2.84- 2.92 (m, 4H), 2.57 (ddd, J= 4.29, 10.55, 14.46 Hz, 1H), 2.15-2.25 (m, 1H), 1.68-1.76 (m, 1H),1.44-1.52 (m, 1H), 1.28-1.44 (m, 3H), 1.18-1.26 (m, 2H), 1.05-1.11 (m,2H) 123

  (S)-2-(4-(cyclopropylsulfonyl)-6-fluoro-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamide SeeCmpd. 10 [M + H] calc'd for C₂₁H₂₂F₂ N₄O₄S₂ 498, found 498 ¹H NMR (400MHz, METHANOL-d₄) δ ppm 1.05-1.13 (m, 2 H) 1.26-1.37 (m, 5 H) 1.45-1.52(m, 1 H) 1.67-1.75 (m, 1 H) 2.17-2.27 (m, 1 H) 2.55 (ddd, J = 14.46,10.42, 4.42 Hz, 1 H) 2.85 (tt, J = 7.96, 4.80 Hz, 1 H) 3.15-3.28 (m, 2H) 3.79-3.91 (m, 2 H) 5.69 (dd, J = 10.61, 5.05 Hz, 1 H) 7.09 (d, J =2.78 Hz, 1 H) 7.57 (dd, J = 8.34, 2.02 Hz, 1 H) 7.87 (dd, J = 9.09, 1.01Hz, 1 H) 8.46 (s, 1 H) 124

  2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(pyrimidin-4-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide See Cmpd. 10[M + H] calc'd for C₂₂H₂₅N₅ O₄S 457, found 457 ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.02-1.12 (m, 2 H) 1.25-1.41 (m, 5 H) 1.41-1.53 (m, 1H) 1.68-1.76 (m, 1 H) 2.18-2.30 (m, 1 H) 2.59 (m, J = 14.31, 10.59,10.59, 3.92 Hz, 1 H) 2.77- 2.87 (m, 1 H) 3.12- 3.27 (m, 2 H) 3.78- 3.91(m, 2 H) 5.62- 5.86 (m, 1 H) 7.58- 7.68 (m, 1 H) 7.70- 7.79 (m, 1 H)8.05- 8.12 (m, 1 H) 8.24 (dd, J = 6.06, 1.26 Hz, 1 H) 8.49 (s, 1 H) 8.66(d, J = 6.06 Hz, 1 H) 8.92 (s, 1 H) 125

  N-(5-cyanothiazol-2-yl )-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M +H] calc'd for C₂₂H₂₃N₅ O₄S₂ 487, found 487 ¹H NMR (400 MHz, METHANOL-d₄)δ ppm 1.01-1.10 (m, 2 H) 1.26-1.42 (m, 5 H) 1.50 (dd, J = 9.35, 2.02 Hz,1 H) 1.70-1.77 (m, 1 H) 2.23-2.32 (m, 1 H) 2.58 (ddd, J = 14.27, 10.61,3.92 Hz, 1 H) 2.81 (tt, J = 7.96, 4.80 Hz, 1 H) 3.15-3.27 (m, 2 H)3.79-3.90 (m, 2 H) 5.77 (dd, J = 10.61, 4.80 Hz, 1 H) 7.62 (dd, J =8.46, 7.20 Hz, 1 H) 7.74 (d, J = 6.57 Hz, 1 H) 8.03-8.07 (m, 2 H) 8.46(s, 1 H) 126

  N-(5-cyanopyrimidin-2-yl)-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M +H] calc'd for C₂₃H₂₄N₆ O₄S 482, found 482 ¹H NMR (400 MHz, METHANOL-d₄)δ ppm 1.02-1.11 (m, 2 H) 1.26-1.41 (m, 5 H) 1.42-1.52 (m, 1 H) 1.70-1.79(m, 1 H) 2.18-2.30 (m, 1 H) 2.53-2.65 (m, 1 H) 2.77-2.87 (m, 1 H)3.12-3.27 (m, 2 H) 3.79-3.91 (m, 2 H) 5.65 (dd, J = 11.37, 4.29 Hz, 1 H)7.63 (dt, J = 8.59, 6.95 Hz, 1 H) 7.74 (dd, J = 6.57, 5.05 Hz, 1 H)7.99- 8.10 (m, 1 H) 8.45 (d, J = 12.88 Hz, 1 H) 8.54 (s, 1 H) 8.95 (s, 1H) 127

  2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 16 & 95 [M + H] calc'd for C₂₀H₂₂FN₅ O₄S₂ 481, found 481 ¹HNMR (400 MHz, METHANOL-d₄) δ ppm 1.10-1.20 (m, 2 H) 1.30-1.43 (m, 5H)1.50-1.57 (m, 1 H) 1.76 (dd, J = 10.23, 1.89 Hz, 1 H) 2.16-2.26 (m, 1 H)2.67 (ddd, J = 14.27, 10.99, 3.79 Hz, 1 H) 2.90 (tt, J = 7.93, 4.71 Hz,1 H) 3.11-3.28 (m, 2 H) 3.81-3.90 (m, 2 H) 6.05 (dd, J = 11.12, 4.29 Hz,1 H) 7.08 (d, J = 2.53 Hz, 1 H) 7.71 (d, J = 4.80 Hz, 1 H) 8.51 (s, 1 H)8.82 (d, 1 H) 128

  (S)-2-(4-(cyclopropylsulfonyl)-6-methoxy-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 10 [M + H] calc'd for C₂₂H₂₆FN₄ O₅S₂ 509, found 509 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 8.52 (s, 1 H), 7.45 (d, J = 1.8 Hz, 1 H),7.00 (br. s., 1 H), 6.96 (s, 1 H), 5.30 (s, 1 H), 3.95 (s, 3 H), 3.78-3.93 (m, 2 H), 3.13- 3.30 (m, 2 H), 2.57- 2.73 (m, 1 H), 2.50 (br. s., 1H), 2.25 (d, J = 5.6 Hz, 1 H), 1.59 (d, J = 12.4 Hz, 1 H), 1.44-1.55 (m,2 H), 1.28-1.44 (m, 4 H), 1.01-1.16 ppm (m, 2 H) 129

  (R)-2-(4-(cyclopropylsulfonyl)-6-methoxy-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 10 [M + H] calc'd for C₂₂H₂₆FN₄ O₅S₂ 509, found 509 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 8.52 (s, 1 H), 7.45 (d, J = 1.8 Hz, 1 H),7.00 (br. s., 1 H), 6.96 (s, 1 H), 5.30 (s, 1 H), 3.95 (s, 3 H),3.78-3.93 (m, 2 H), 3.13-3.30 (m, 2 H), 2.57-2.73 (m, 1 H), 2.50 (br.s., 1 H), 2.25 (d, J = 5.6 Hz, 1 H), 1.59 (d, J = 12.4 Hz, 1 H),1.44-1.55 (m, 2 H), 1.28-1.44 (m, 4 H), 1.01-1.16 ppm (m, 2 H) 130

  2-(4-(cyclopropylsulfonyl)-6-hydroxy-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 12 [M + H] calc'd for C₂₁H₂₄FN₄ O₅S₂ 495, found 495 ¹H NMR(DMSO-d₆, 400 MHz): δ = 12.70 (s, 1 H), 10.48 (s, 1 H), 8.23 (s, 1 H),7.33-7.36 (m, 2 H), 7.23 (d, J = 1.8 Hz, 1 H), 5.62 (d, J = 4.3 Hz, 1H), 3.71- 3.85 (m, 3 H), 3.06- 3.21 (m, 2 H), 2.24- 2.41 (m, 1 H), 2.09-2.24 (m, 1 H), 1.54- 1.63 (m, 1 H), 1.48 (br. s., 1 H), 1.28 (br. s., 3H), 1.16 (br. s., 2 H), 1.06 ppm (dd, J = 7.8, 2.0 Hz, 2 H) 131

  2-(4-(cyclopropylsulfonyl)-6-hydroxy-2H-indazol-2-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamideSee Cmpd. 12 [M + H] calc'd for C₂₁H₂₄FN₄ O₅S₂ 495, found 495 ¹H NMR(DMSO-d₆, 400 MHz): δ = 13.41 (br.s., 1H), 12.74 (s, 1 H), 8.21 (s, 1H), 7.35 (d, J = 2.5 Hz, 1 H), 7.30 (d, J = 2.0 Hz, 1 H), 7.21 (d, J =1.0 Hz, 1 H), 5.18 (d, J = 9.3 Hz, 1 H), 3.79-3.87 (m, 2 H), 3.21-3.35(m, 2 H), 2.93-3.02 (m, 1 H), 1.92-2.00 (m, 1 H), 1.84 (d, J = 3.5 Hz, 1H), 1.82 (br. s., 1 H), 1.64 (br. s., 2 H), 1.28 (br. s., 2 H),1.14-1.19 (m, 2 H), 1.00-1.06 ppm (m, 2 H) 132

  (R)-2-(6-cyano-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M + H] calc'd forC₂₂H₂₂FN₅ O₄S₂ 505, found 505 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm1.07-1.14 (m, 2 H) 1.27-1.45 (m, 5 H) 1.46-1.53 (m, 1 H) 1.68-1.76 (m, 1H) 2.23-2.32 (m, 1 H) 2.60 (ddd, J = 14.46, 10.42, 4.42 Hz, 1 H) 2.89(tt, J = 7.96, 4.80 Hz, 1 H) 3.16-3.28 (m, 2 H) 3.80-3.91 (m, 2 H) 5.83(dd, J = 10.61, 5.05 Hz, 1 H) 7.10 (d, J = 2.78 Hz, 1 H) 7.99 (d, J =1.26 Hz, 1 H) 8.59 (s, 1 H) 8.64 (s, 1 H) 133

  (S)-2-(6-cyano-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 10 [M + H] calc'd for C₂₂H₂₂FN₅ O₄S₂ 505, found 505 ¹H NMR(400 MHz, METHANOL-d₄) δ ppm 1.07-1.14 (m, 2 H) 1.27-1.45 (m, 5 H)1.46-1.53 (m, 1 H) 1.68-1.76 (m, 1 H) 2.23-2.32 (m, 1 H) 2.60 (ddd, J =14.46, 10.42, 4.42 Hz, 1 H) 2.89 (tt, J = 7.96, 4.80 Hz, 1 H) 3.16-3.28(m, 2 H) 3.80-3.91 (m, 2 H) 5.83 (dd, J = 10.61, 5.05 Hz, 1 H) 7.10 (d,J = 2.78 Hz, 1 H) 7.99 (d, J = 1.26 Hz, 1 H) 8.59 (s, 1 H) 8.64 (s, 1 H)134

  2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamide SeeCmpd. 10 [M + H] calc'd for C₂₃H₂₉N₅ O₄S 473, found 473 ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.01-1.09 (m, 2 H) 1.25-1.43 (m, 5 H) 1.51 (d, J =9.35 Hz, 1 H) 1.71 (d, J = 11.87 Hz, 1 H) 2.17-2.28 (m, 4 H) 2.57 (ddd,J = 14.15, 10.36, 4.04 Hz, 1 H) 2.81 (tt, J = 7.96, 4.80 Hz, 1 H)3.14-3.28 (m, 2 H) 3.63-3.69 (m, 3 H) 3.80-3.90 (m, 2 H) 5.66 (dd, J =10.36, 5.05 Hz, 1 H) 6.24 (s, 1 H) 7.61-7.66 (m, 1 H) 7.74 (d, J = 6.57Hz, 1 H) 8.08 (d, J = 8.34 Hz, 1 H) 8.48 (s, 1 H) 135

  N-(5-cyanopyridin-2-yl)-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M +H] calc'd for C₂₄H₂₅N₅ O₄S 481, found 481 ¹H NMR (400 MHz, METHANOL-d₄)δ ppm 1.01-1.09 (m, 2 H) 1.25-1.43 (m, 5 H) 1.50 (dd, J = 9.47, 1.89 Hz,1 H) 1.72 (d, J = 12.13 Hz, 1 H) 2.18-2.27 (m, 1 H) 2.60 (ddd, J =14.15, 10.48, 3.92 Hz, 1 H) 2.81 (tt, J = 7.96, 4.80 Hz, 1 H) 3.13- 3.27(m, 2 H) 3.79- 3.90 (m, 2 H) 5.79 (dd, J = 10.48, 4.93 Hz, 1 H) 7.63(dd, J = 8.59, 7.33 Hz, 1 H) 7.74 (d, J = 6.57 Hz, 1 H) 8.04- 8.12 (m, 2H) 8.24 (d, J = 8.84 Hz, 1 H) 8.49 (s, 1 H) 8.60-8.64 (m, 1 H) 136

  (S)-N-(5-cyanothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide See Cmpd. 10[M + H] calc'd for C₂₂H₂₃N₅ O₄S₂ 487, found 487 ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.01-1.10 (m, 2 H) 1.26-1.42 (m, 5 H) 1.50 (dd, J =9.35, 2.02 Hz, 1 H) 1.70-1.77 (m, 1 H) 2.23-2.32 (m, 1 H) 2.58 (ddd, J =14.27, 10.61, 3.92 Hz, 1 H) 2.81 (tt, J = 7.96, 4.80 Hz, 1 H) 3.15-3.27(m, 2 H) 3.79-3.90 (m, 2 H) 5.77 (dd, J = 10.61, 4.80 Hz, 1 H) 7.62 (dd,J = 8.46, 7.20 Hz, 1 H) 7.74 (d, J = 6.57 Hz, 1 H) 8.03-8.07 (m, 2 H)8.46 (s, 1 H) 137

  (R)-N-(5-cyanothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide [M + H] calc'dfor C₂₂H₂₃N₅ O₄S₂ 487, found 487 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm1.01-1.10 (m, 2 H) 1.26-1.42 (m, 5 H) 1.50 (dd, J = 9.35, 2.02 Hz, 1 H)1.70-1.77 (m, 1 H) 2.23-2.32 (m, 1 H) 2.58 (ddd, J = 14.27, 10.61, 3.92Hz, 1 H) 2.81 (tt, J = 7.96, 4.80 Hz, 1 H) 3.15- 3.27 (m, 2 H) 3.79-3.90(m, 2 H) 5.77 (dd, J = 10.61, 4.80 Hz, 1 H) 7.62 (dd, J = 8.46, 7.20 Hz,1 H) 7.74 (d, J = 6.57 Hz, 1 H) 8.03- 8.07 (m, 2 H) 8.46 (s, 1 H) 138

  (S)-2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 16 & 95 [M + H] calc'd for C₂₀H₂₂FN₅O₄S₂ 481, found 481 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.10-1.20 (m, 2H) 1.30-1.43 (m, 5 H) 1.50-1.57 (m, 1 H) 1.76 (dd, J = 10.23, 1.89 Hz, 1H) 2.16-2.26 (m, 1 H) 2.67 (ddd, J = 14.27, 10.99, 3.79 Hz, 1 H) 2.90(tt, J = 7.93, 4.71 Hz, 1 H) 3.11-3.28 (m, 2 H) 3.81-3.90 (m, 2 H) 6.05(dd, J = 11.12, 4.29 Hz, 1 H) 7.08 (d, J = 2.53 Hz, 1 H) 7.71 (d, J =4.80 Hz, 1 H) 8.51 (s, 1 H) 8.82 (d, 1 H) 139

  (R)-2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 16 & 95 [M + H] calc'd for C₂₀H₂₂FN₅O₄S₂ 481, found 481 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.10-1.20 (m, 2H) 1.30-1.43 (m, 5 H) 1.50-1.57 (m, 1 H) 1.76 (dd, J = 10.23, 1.89 Hz, 1H) 2.16-2.26 (m, 1 H) 2.67 (ddd, J = 14.27, 10.99, 3.79 Hz, 1 H) 2.90(tt, J = 7.93, 4.71 Hz, 1 H) 3.11- 3.28 (m, 2 H) 3.81- 3.90 (m, 2 H)6.05 (dd, J = 1.12, 4.29 Hz, 1 H) 7.08 (d, J = 2.53 Hz, 1 H) 7.71 (d, J= 4.80 Hz, 1 H) 8.51 (s, 1 H) 8.82 (d, 1 H) 140

  2-(4-(cyclopropylsulfonyl)-2H-pyrazolo[3,4-c]pyridin-2-yl)-N-(5-fluoro- thiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 13 [M + H] calc'd for C₂₀H₂₃FN₅ O₄S₂480, found 480 141

  (S)-2-(6-chloro-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 10 [M + H] calc'd for C₂₁H₂₃ClF N₄O₄S₂ 514.0, found 514.0 142

  2-(6-amino-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 21 [M + H] calc'd for C₂₁H₂₅FN₅ O₄S₂ 494.1, found 494.4 143

  2-(4-(cyclopropylsulfonyl)-6-(difluoromethoxy)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 12 [M + H] calc'd for C₂₂H₂₄F₃N₄O₅S₂ 545.1, found 545.3 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.03-1.14(m, 2 H) 1.23-1.45 (m, 5 H) 1.45-1.55 (m, 1 H) 1.72 (dd, J = 12.51, 2.40Hz, 1 H) 2.16-2.31 (m, 1 H) 2.55 (ddd, J = 14.46, 10.42, 4.42 Hz, 1 H)2.86 (tt, J = 7.83, 4.80 Hz, 1 H) 3.22 (m, J = 17.15, 11.57, 11.57, 2.15Hz, 2 H) 3.76-3.96 (m, 2 H) 7.01 (d, J = 73.01 Hz, 1 H) 7.10 (d, J =2.53 Hz, 1 H) 7.56 (d, J = 1.77 Hz, 1 H) 7.87 (s, 1 H) 8.47 (s, 1 H) 144

  2-(4-(cyclopropylsulfonyl)-5-hydroxy-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran- 4-yl)propanamideSee Cmpd. 10 [M + H] calc'd for C₂₁H₂₄FN₄ O₅S₂ 495.1, found 495.3 145

  (R)-2-(6-chloro-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M + H] calc'd forC₂₁H₂₃ClF N₄O₄S₂ 514.0, found 514.0 146

  2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(1-(methyl-sulfonyl)-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamide SeeCmpd. 10 [M + H] calc'd for C₂₂H₂₈N₅ O₆S₂ 522.1, found 522.1 ¹H NMR (400MHz, CHLOROFORM-d) δ 9.00 (s, 1H), 8.66 (s, 1H), 7.92 (d, J = 3.03 Hz,1H), 7.81 (d, J = 6.57 Hz, 1H), 7.74 (d, J = 8.84 Hz, 1H), 7.61 (dd, J =7.33, 8.59 Hz, 1H), 7.02 (d, J = 2.78 Hz, 1H), 5.38 (dd, J = 5.05, 10.61Hz, 1H), 3.89 (br. s., 2H), 3.09-3.30 (m, 5H), 2.60-2.71 (m, 1H),2.46-2.59 (m, 1H), 2.29 (ddd, J = 5.05, 8.65, 14.08 Hz, 1H), 1.28-1.55(m, 6H), 1.25 (br. s., 1H), 1.01-1.20 (m, 2H) 147

  2-(4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(6-fluoropyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl) propanamide See Cmpd.10 [M + H] calc'd for C₂₃H₂₆FN₄ O₄S 473.2, found 473.2 ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.92 (s, 1H), 8.67 (s, 1H), 8.04 (dd, J = 1.64, 7.96 Hz,1H), 7.73-7.86 (m, 3H), 7.60 (dd, J = 7.33, 8.59 Hz, 1H), 6.68 (dd, J =2.27, 8.08 Hz, 1H), 5.39 (dd, J = 4.93, 10.48 Hz, 1H), 3.81-3.97 (m,2H), 3.11-3.34 (m, 3H), 2.46-2.70 (m, 2H), 2.29 (ddd, J = 4.93, 8.59,14.02 Hz, 1H), 1.62 (d, J = 12.88 Hz, 1H), 1.31- 1.55 (m, 4H), 1.26 (qd,J = 4.29, 7.66 Hz, 1H), 0.96-1.15 (m, 2H) 148

  2-(4-(cyclopropylsulfonyl)-5-fluoro-2H-indazol-2-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 19 [M + H] calc'd forC₂₁H₂₃F₂N₄ O₄S₂ 497.1, found 497.1 ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.61(s, 1H), 8.04 (dd, J = 4.17, 9.22 Hz, 1H), 7.24-7.35 (m, 2H), 7.03 (br.s., 1H), 5.34 (dd, J = 5.43, 9.98 Hz, 1H), 3.91 (br. s., 2H), 3.18-3.34(m, 2H), 2.80-2.97 (m, 1H), 2.37-2.53 (m, 1H), 2.20-2.37 (m, 1H), 1.68(br. s., 1H), 1.45-1.55 (m, 2H), 1.26-1.45 (m, 4H), 1.00-1.15 (m, 2H)149

  2-(4-(cyclopropylsulfonyl)-5-fluoro-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 19 [M + H] calc'd for C₂₁H₂₃F₂N₄ O₄S₂ 497.1, found 497.1 ¹HNMR (400 MHz, CHLOROFORM-d) δ 8.72 (s, 1H), 7.73 (dd, J = 2.91, 9.22 Hz,1H), 7.37 (t, J = 9.35 Hz, 1H), 7.07 (d, J = 2.27 Hz, 1H), 5.46 (dd, J =4.93, 10.48 Hz, 1H), 3.92 (ddd, J = 2.53, 11.37, 13.39 Hz, 2H), 3.14-3.31 (m, 2H), 2.83- 2.94 (m, 1H), 2.45- 2.61 (m, 1H), 2.28 (ddd, J =4.93, 8.78, 14.08 Hz, 1H), 1.58- 1.69 (m, 1H), 1.32- 1.58 (m, 5H), 1.21(d, J = 3.79 Hz, 1H), 1.04-1.17 (m, 2H) 150

  2-(5-bromo-4-(cyclopropylsulfonyl)-1H-indazol-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 19 [M + H] calc'd for C₂₁H₂₃BrF N₄O₄S₂ 558, found 558 ¹H NMR(400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 7.82 (d, J = 7.58 Hz, 1H), 7.56 (d, J= 7.58 Hz, 1H), 7.38 (d, J = 2.53 Hz, 1H), 5.82 (dd, J = 5.68, 9.73 Hz,1H), 3.73-3.86 (m, 2H), 3.09-3.20 (m, 2H), 2.89-3.04 (m, 1H), 2.45-2.61(m, 1H) 2.20-2.36 (m, 1H), 1.64 (d, J = 7.83 Hz, 1H), 1.51 (d, J = 13.14Hz, 1H), 1.20-1.37 (m, 5H), 0.97-1.09 (m, 2H) 151

  2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 13 [M + H] calc'd for C₂₁H₂₆N₆ O₄S460, found 460 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03-1.13 (m, 2 H)1.17-1.36 (m, 5 H) 1.48-1.70 (m, 2 H) 2.28 (d, J = 6.82 Hz, 1 H) 2.44(br. s., 1 H) 3.03-3.23 (m, 3 H) 3.69-3.84 (m, 5 H) 5.87 (d, J = 3.54Hz, 1 H) 6.37 (d, J = 2.02 Hz, 1 H) 7.55 (d, J = 2.02 Hz, 1 H) 8.51 (s,1 H) 8.68 (s, 1 H) 9.67 (s, 1 H) 11.08 (s, 1 H) 152

  2-(4-(cyclopropylsulfonyl)-5-fluoro-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamide SeeCmpd. 22 [M + H] calc'd for C₂₂H₂₇FN₅ O₄S 476, found 476 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 8.58- 8.83 (m, 2H), 7.74 (dd, J = 9.1, 3.0Hz, 1 H), 7.34 (t, J = 9.3 Hz, 1 H), 7.23 (d, J = 2.0 Hz, 1 H), 6.61 (d,J = 2.3 Hz, 1 H), 5.33 (dd, J = 10.4, 5.1 Hz, 1 H), 3.81-3.94 (m, 2 H),3.76 (s, 3 H), 3.08- 3.32 (m, 2 H), 2.90 (dd, J = 4.8, 3.3 Hz, 1 H),2.49 (d, J = 3.8 Hz, 1 H), 2.22-2.37 (m, 1 H), 1.59 (d, J = 12.4 Hz, 1H), 1.19- 1.55 (m, 5 H), 1.04- 1.19 (m, 2 H), 0.78- 0.93 ppm (m, 1 H)153

  2-(4-(cyclopropylsulfonyl)-5-fluoro-2H-indazol-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 22 [M + H] calc'd for C₂₂H₂₇FN₅ O₄S476, found 476 ¹H NMR (CHLOROFORM-d, 400 MHz): δ = 9.16 (s, 1 H), 8.59(s, 1 H), 8.04 (dd, J = 9.3, 3.5 Hz, 1 H), 7.28 (d, 1 H), 7.24 (d, J =2.5 Hz, 1 H), 6.63 (d, J = 2.3 Hz, 1 H), 5.27 (dd, J = 9.9, 5.6 Hz, 1H), 3.93 (dd, J = 11.4, 2.3 Hz, 1 H), 3.87 (d, J = 10.9 Hz, 1 H), 3.77(s, 3 H), 3.23- 3.37 (m, 2 H), 2.78- 2.94 (m, 1 H), 2.42 (dd, J = 9.6,4.5 Hz, 1 H), 2.27-2.37 (m, 1 H), 1.59-1.84 (m, 2 H), 1.28-1.52 (m, 5H), 0.95-1.18 ppm (m, 2 H) 154

  2-(4-(cyclopropylsulfonyl)-5-fluoro-1H-indazol-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamide See Cmpd.22 [M + H] calc'd for C₂₂H₂₅FN₅ O₄S 474, found 474 ¹H NMR (CHLOROFORM-d,400 MHz): δ = 9.39- 9.52 (m, 1 H), 9.05 (s, 1 H), 8.80 (s, 1 H),8.31-8.40 (m, 1 H), 8.18-8.29 (m, 1 H), 7.77 (dd, J = 9.2, 2.9 Hz, 1 H),7.39 (t, J = 9.5 Hz, 1 H), 5.39 (dd, J = 10.4, 5.1 Hz, 1 H), 3.76-4.00(m, 2 H), 3.09-3.34 (m, 2 H), 2.74-2.96 (m, 1 H), 2.43-2.62 (m, 1 H),2.19-2.43 (m, 1 H), 1.57-1.66 (m, 1 H), 1.24-1.55 (m, 6 H), 1.03-1.19ppm (m, 2 H) 155

  2-(4-(cyclopropylsulfonyl)-5-fluoro-1H-indazol-1-yl)-N-(1-ethyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 22 [M + H] calc'd for C₂₃H₂₉FN₅ O₄S 490, found 490 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 9.38 (s, 1H), 8.71 (s, 1H), 7.75-7.78 (m,1H), 7.23-7.36 (m, 2 H), 6.67-6.72 (m, 1 H), 5.25-5.46 (m, 1 H),4.00-4.12 (m, 2 H), 3.83-3.95 (m, 2 H), 3.12-3.34 (m, 2 H), 2.81-2.94(m, 1 H), 2.39-2.59 (m, 1 H), 2.23-2.39 (m, 1 H), 1.32-1.54 (m, 10 H),0.96-1.19 ppm (m, 2 H) 156

  2-(4-(cyclopropylsulfonyl)-5-fluoro-2H-indazol-2-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamide SeeCmpd. 22 [M + H] calc'd for C₂₂H₂₅FN₅ O₄S 474, found 474 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 9.53 (s, 2 H), 8.81 (s, 1 H), 8.42 (d, J =3.0 Hz, 2 H), 7.78 (dd, J = 9.0, 3.4 Hz, 1 H), 7.41 (t, J = 9.5 Hz, 1H), 5.43 (dd, J = 10.1, 5.3 Hz, 1 H), 3.89-4.13 (m, 2 H), 3.18-3.42 (m,2 H), 2.78-2.96 (m, 1 H), 2.52 (dd, J = 9.9, 4.5 Hz, 1 H), 2.21- 2.41(m, 1 H), 1.65 (d, J = 12.6 Hz, 1 H), 1.38-1.56 (m, 5 H), 1.31-1.37 (m,1 H), 1.11-1.24 ppm (m, 2 H) 157

  2-(4-(cyclopropylsulfonyl)-5-methyl-1H-indazol-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H-pyran- 4-yl)propanamide SeeCmpd. 22 [M + H] calc'd for C₂₃H₂₈N₅ O₄S 470, found 470 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 9.53 (br. s., 1H), 9.31 (br. s., 1 H), 8.77(s, 1 H), 8.27-8.50 (m, 2 H), 7.64 (d, J = 8.6 Hz, 1 H), 7.43 (d, J =8.8 Hz, 1 H), 5.38 (dd, J = 10.4, 5.1 Hz, 1 H), 3.80-4.00 (m, 2 H),3.11-3.34 (m, 2 H), 2.86 (s, 3 H), 2.69 (tt, J = 8.0, 4.8 Hz, 1 H),2.44-2.60 (m, 1 H), 2.29 (ddd, J = 13.9, 8.3, 5.1 Hz, 1 H), 1.62 (d, J =12.6 Hz, 1 H), 1.34-1.55 (m, 5 H), 1.25-1.33 (m, 1 H), 0.96-1.14 ppm (m,2 H 158

  2-(4-(cyclopropylsulfonyl)-5-methyl-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 22 [M + H] calc'd for C₂₃H₃₀N₅ O₄S472, found 472 ¹H NMR (CHLOROFORM-d, 400 MHz): δ = 9.26 (s, 1 H), 8.67(s, 1 H), 7.64 (d, J = 8.8 Hz, 1 H), 7.38 (d, J = 8.6 Hz, 1 H),7.15-7.32 (m, 1 H), 6.67 (d, J = 2.5 Hz, 1 H), 5.34 (dd, J = 10.5, 4.9Hz, 1 H), 3.88 (td, J = 11.2, 2.7 Hz, 2 H), 3.78 (s, 3 H), 3.08-3.31 (m,2 H), 2.85 (s, 3 H), 2.60-2.80 (m, 1 H), 2.39-2.60 (m, 1 H), 2.27 (ddd,J = 14.0, 8.5, 5.1 Hz, 1 H), 1.62 (d, J = 12.6 Hz, 1 H), 1.30-1.51 (m, 5H), 1.21-1.29 (m, 1 H), 1.03 (d, J = 7.3 Hz, 1 H), 1.02 ppm (s, 1 H) 159

  (S)-2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 13 [M + H] calc'd forC₂₁H₂₆N₆ O₄S 460, found 460 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03-1.13(m, 2 H) 1.17-1.36 (m, 5 H) 1.48-1.70 (m, 2 H) 2.28 (d, J = 6.82 Hz, 1H) 2.44 (br. s., 1 H) 3.03-3.23 (m, 3 H) 3.69-3.84 (m, 5 H) 5.87 (d, J =3.54 Hz, 1 H) 6.37 (d, J = 2.02 Hz, 1 H) 7.55 (d, J = 2.02 Hz, 1 H) 8.51(s, 1 H) 8.68 (s, 1 H) 9.67 (s, 1 H) 11.08 (s, 1 H) 160

  (R)-2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 13 [M + H]calc'd for C₂₁H₂₆N₆ O₄S 460, found 460 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.03-1.13 (m, 2 H) 1.17-1.36 (m, 5 H) 1.48-1.70 (m, 2 H) 2.28 (d, J =6.82 Hz, 1 H) 2.44 (br. s., 1 H) 3.03-3.23 (m, 3 H) 3.69-3.84 (m, 5 H)5.87 (d, J = 3.54 Hz, 1 H) 6.37 (d, J = 2.02 Hz, 1 H) 7.55 (d, J = 2.02Hz, 1 H) 8.51 (s, 1 H) 8.68 (s, 1 H) 9.67 (s, 1 H) 11.08 (s, 1 H) 161

  (R)-2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 16 & 92 [M + H] calc'd for C₂₁H₂₄N₆ O₄S 458, found 458 ¹H NMR(400 MHz, METHANOL-d₄) δ ppm 1.09-1.19 (m, 2 H) 1.33-1.46 (m, 5 H) 1.56(dd, J = 9.47, 1.89 Hz, 1 H) 1.76 (dd, J = 9.73, 1.89 Hz, 1 H) 2.20-2.30(m, 1 H) 2.73 (ddd, J = 14.15, 11.12, 3.54 Hz, 1 H) 2.91 (tt, J = 7.96,4.80 Hz, 1 H) 3.11-3.28 (m, 2 H) 3.81-3.90 (m, 2 H) 6.10 (dd, J = 11.12,4.29 Hz, 1 H) 7.71 (d, J = 4.55 Hz, 1 H) 8.31 (d, J = 2.53 Hz, 1 H) 8.36(dd, J = 2.53, 1.52 Hz, 1 H) 8.53 (s, 1 H) 8.83 (d, J = 4.80 Hz, 1 H)9.29 (s, 1 H) 162

  (S)-2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamideSee Cmpd. 16 & 92 [M + H] calc'd for C₂₁H₂₄N₆ O₄S 458, found 458 ¹H NMR(400 MHz, METHANOL-d₄) δ ppm 1.09-1.19 (m, 2 H) 1.33-1.46 (m, 5 H) 1.56(dd, J = 9.47, 1.89 Hz, 1 H) 1.76 (dd, J = 9.73, 1.89 Hz, 1 H) 2.20-2.30 (m, 1 H) 2.73 (ddd, J = 14.15, 11.12, 3.54 Hz, 1 H) 2.91 (tt, J =7.96, 4.80 Hz, 1 H) 3.11- 3.28 (m, 2 H) 3.81- 3.90 (m, 2 H) 6.10 (dd, J= 11.12, 4.29 Hz, 1 H) 7.71 (d, J = 4.55 Hz, 1 H) 8.31 (d, J = 2.53 Hz,1 H) 8.36 (dd, J = 2.53, 1.52 Hz, 1 H) 8.53 (s, 1 H) 8.83 (d, J = 4.80Hz, 1 H) 9.29 (s, 1 H) 163

  (R)-2-(6-amino-4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 16 [M + H] calc'd forC₂₁H₂₅N₇ O₄S 473, found 473 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm0.99-1.06 (m, 2 H) 1.29-1.42 (m, 5 H) 1.52 (d, J = 9.35 Hz, 1 H)1.71-1.79 (m, 1 H) 2.13-2.23 (m, 1 H) 2.57-2.66 (m, 1 H) 2.90 (tt, J =7.96, 4.80 Hz, 1 H) 3.13- 3.27 (m, 2 H) 3.86 (t, J = 10.74 Hz, 2 H) 5.90(dd, J = 10.99, 4.42 Hz, 1 H) 8.17 (s, 1 H) 8.27- 8.38 (m, 3 H) 9.31 (s,1 H) 164

  (S)-2-(6-amino-4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 16 [M + H]calc'd for C₂₁H₂₅N₇ O₄S 473, found 473 ¹H NMR (400 MHz, METHANOL-d₄) δppm 0.99-1.06 (m, 2 H) 1.29-1.42 (m, 5 H) 1.52 (d, J = 9.35 Hz, 1 H)1.71-1.79 (m, 1 H) 2.13-2.23 (m, 1 H) 2.57-2.66 (m, 1 H) 2.90 (tt, J =7.96, 4.80 Hz, 1 H) 3.13-3.27 (m, 2 H) 3.86 (t, J = 10.74 Hz, 2 H) 5.90(dd, J = 10.99, 4.42 Hz, 1 H) 8.17 (s, 1 H) 8.27- 8.38 (m, 3 H) 9.31 (s,1 H) 165

  (S)-2-(4-(cyclopropylsulfonyl)-5-fluoro-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamideSee Cmpd. 22 [M + H] calc'd for C₂₂H₂₇FN₅ O₄S 476, found 476 ¹H NMR(CHLOROFORM-d, 400 MHz): δ = 8.58- 8.83 (m, 2 H), 7.74 (dd, J = 9.1, 3.0Hz, 1 H), 7.34 (t, J = 9.3 Hz, 1 H), 7.23 (d, J = 2.0 Hz, 1 H), 6.61 (d,J = 2.3 Hz, 1 H), 5.33 (dd, J = 10.4, 5.1 Hz, 1 H), 3.81- 3.94 (m, 2 H),3.76 (s, 3 H), 3.08-3.32 (m, 2 H), 2.90 (dd, J = 4.8, 3.3 Hz, 1 H), 2.49(d, J = 3.8 Hz, 1 H), 2.22-2.37 (m, 1 H), 1.59 (d, J = 12.4 Hz, 1 H),1.19- 1.55 (m, 5 H), 1.04- 1.19 (m, 2 H), 0.78- 0.93 ppm (m, 1 H) 166

  (R)-2-(4-(cyclopropylsulfonyl)-5-fluoro-1H-indazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 22 [M + H] calc'd for C₂₂H₂₇FN₅ O₄S476, found 476 ¹H NMR (CHLOROFORM-d, 400 MHz): δ = 8.58- 8.83 (m, 2 H),7.74 (dd, J = 9.1, 3.0 Hz, 1 H), 7.34 (t, J = 9.3 Hz, 1 H), 7.23 (d, J =2.0 Hz, 1 H), 6.61 (d, J = 2.3 Hz, 1 H), 5.33 (dd, J = 10.4, 5.1 Hz, 1H), 3.81-3.94 (m, 2 H), 3.76 (s, 3 H), 3.08- 3.32 (m, 2 H), 2.90 (dd, J= 4.8, 3.3 Hz, 1 H), 2.49 (d, J = 3.8 Hz, 1 H), 2.22-2.37 (m, 1 H), 1.59(d, J = 12.4 Hz, 1 H), 1.19-1.55 (m, 5 H), 1.04-1.19 (m, 2 H), 0.78-0.93ppm (m, 1 H) 167

  2-(6-chloro-4-(cyclopropylsulfonyl)-2H-indazol-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 10 [M + H] calc'd for C₂₂H₂₇ClN₅ O₄S492, found 492 ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.17 (s, 1H), 8.47 (d, J= 1.01 Hz, 1H), 8.04 (d, J = 1.01 Hz, 1H), 7.69 (d, J = 1.77 Hz, 1H),7.18-7.31 (m, 1H), 6.62 (d, J = 2.27 Hz, 1H), 5.26 (dd, J = 5.81, 9.85Hz, 1H), 3.82-4.00 (m, 2H), 3.72-3.81 (m, 3H), 3.26 (td, J = 1.89, 11.43Hz, 2H), 2.48-2.62 (m, 1H), 2.25-2.48 (m, 2H), 1.61-1.76 (m, 1H),1.47-1.55 (m, 1H), 1.26-1.47 (m, 5H), 0.97-1.11 (m, 2H) 168

  2-(6-chloro-4-(cyclopropylsulfonyl)-2H-indazol-2-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H-pyran-4- yl)propanamide SeeCmpd. 10 [M + H] calc'd for C₂₂H₂₅ClN₅ O₄S 490.1, found 490.1 ¹H NMR(400 MHz, CHLOROFORM-d) δ 9.59 (s, 1H), 9.49 (br. s., 1H), 8.52 (s, 1H),8.38 (br. s., 1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.71 (d, J = 1.52 Hz,1H), 5.33 (dd, J = 5.81, 9.85 Hz, 1H), 3.81-4.02 (m, 2H), 3.18-3.32 (m,2H), 2.42-2.66 (m, 2H), 2.26-2.42 (m, 1H), 1.70 (d, J = 12.13 Hz, 1H),1.62 (br. s., 1H), 1.49-1.58 (m, 1H), 1.29-1.49 (m, 4H), 1.00-1.14 (m,2H) 169

  2-(4-(cyclopropylsulfonyl)-2H-pyrazolo[3,4-c]pyridin-2-yl)-N-(pyrazin-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamideSee Cmpd. 13 & 140 [M + H] calc'd for C₂₁H₂₄N₆ O₄S 458, found 458 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.04-1.14 (m, 2 H) 1.17-1.40 (m, 5 H) 1.48-1.71(m, 2 H) 2.23-2.35 (m, 1 H) 2.53-2.60 (m, 1 H) 3.02-3.21 (m, 3 H)3.70-3.88 (m, 2 H) 5.97 (dd, J = 9.85, 5.56 Hz, 1 H) 8.38- 8.49 (m, 2 H)8.57 (s, 1 H) 9.00 (s, 1 H) 9.27 (d, J = 1.26 Hz, 1 H) 9.56 (s, 1 H)11.56 (s, 1 H) 170

  2-(6-amino-4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide See Cmpd. 16 [M + H] calc'd forC₂₁H₂₇N₇ O₄S 475, found 475 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm1.11-1.19 (m, 2 H) 1.28-1.44 (m, 5 H) 1.49-1.56 (m, 1 H) 1.73-1.81 (m, 1H) 2.24 (ddd, J = 13.77, 8.97, 4.55 Hz, 1 H) 2.67-2.77 (m, 1 H)2.85-2.95 (m, 1 H) 3.10-3.28 (m, 2 H) 3.79-3.90 (m, 5 H) 6.08 (dd, J =11.37, 4.29 Hz, 1 H) 7.72 (d, J = 4.80 Hz, 1 H) 7.75 (s, 1 H) 8.53 (s, 1H) 8.84 (d, 1 H) 171

  (S)-2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro-2H- pyran-4-yl)propanamideSee Cmpd. 20 [M + H] calc'd for C₂₁H₂₅N₆ O₄S 458, found 458 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.06-1.12 (m, 2 H) 1.20-1.37 (m, 5 H) 1.50 (d, J =11.62 Hz, 1 H) 1.66 (d, J = 11.12 Hz, 1 H) 2.25-2.35 (m, 1 H) 2.52-2.58(m, 1 H) 3.04-3.17 (m, 3 H) 3.71-3.83 (m, 2 H) 6.06 (dd, J = 10.11, 5.31Hz, 1 H) 8.40 (d, J = 2.53 Hz, 1 H) 8.42-8.46 (m, 1 H) 8.55 (s, 1 H)8.70 (s, 1 H) 9.24 (d, J =1.26 Hz, 1 H) 9.68 (s, 1 H). 172

  (R)-2-(4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(pyrazin-2-yl)-3-(tetrahydro- 2H-pyran-4-yl)propanamideSee Cmpd. 20 [M + H] calc'd for C₂₁H₂₅N₆ O₄S 458, found 458 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.06-1.12 (m, 2 H) 1.20-1.37 (m, 5 H) 1.50 (d, J =11.62 Hz, 1 H) 1.66 (d, J = 11.12 Hz, 1 H) 2.25-2.35 (m, 1 H) 2.52-2.58(m, 1 H) 3.04-3.17 (m, 3 H) 3.71-3.83 (m, 2 H) 6.06 (dd, J = 10.11, 5.31Hz, 1 H) 8.40 (d, J = 2.53 Hz, 1 H) 8.42-8.46 (m, 1 H) 8.55 (s, 1 H)8.70 (s, 1 H) 9.24 (d, J = 1.26 Hz, 1 H) 9.68 (s, 1 H).

Biological Testing

The activity of compounds as glucokinase activators may be assayed invitro, in vivo or in a cell line. Provided below is an enzymaticglucokinase activity assay.

Purified glucokinase may be obtained as follows. DNA encoding residues12-465 of the full-length sequence of the human enzyme may be amplifiedby PCR and cloned into the HindIII and EcoRI sites of pFLAG-CTC (Sigma).SEQ. I.D. No. 1 corresponds to residues 12-465 of glucokinase.

The expression of recombinant glucokinase protein may be carried out bytransformation and growth of DH10b-T1r E. coli cells incorporating the(pFLAG-CTC) plasmid in LB media. Protein expression can be induced inthis system by the addition of IPTG to the culture medium.

Recombinant protein may be isolated from cellular extracts by passageover Sepharose Q Fast Flow resin (Pharmacia). This partially purified GKextract may then be further purified by a second passage over Poros HQ10(Applied Biosystems). The purity of GK may be determined on denaturingSDS-PAGE gel. Purified GK may then be concentrated to a finalconcentration of 20.0 mg/ml. After flash freezing in liquid nitrogen,the proteins can be stored at −78° C. in a buffer containing 25 mMTRIS-HCl pH 7.6, 50 mM NaCl, and 0.5 mM TCEP.

It should be noted that a variety of other expression systems and hostsare also suitable for the expression of glucokinase, as would be readilyappreciated by one of skill in the art.

The activation properties of compounds for GK may be determined using ablack 384-well-plate format under the following reaction conditions: 25mM Hepes pH 7.2, 25 mM NaCl, 10 mM MgCl₂, 0.01% Brij35, 1 mM DTT, 5 μMATP, 5 mM Glucose 2% DMSO. The amount of ATP consumed may be determinedquantitatively by addition of equal volume of luciferase reagent(luciferase+beetle luciferin—KinaseGlo Luminescent Kinase Assay kit fromPromega). The luminescence intensity may be measured by using theAnalyst HT from LJL Biosystems.

The assay reaction may be initiated as follows: 4 μl of substratemixture (12.5 μM ATP and 12.5 mM Glucose) was added to each well of theplate, followed by the addition of 2 μl of activator (2 fold serialdilutions for 11 data points for each activator) containing 10% DMSO. 4μL of 1.25 nM GK solution may be added to initiate the reaction. Thereaction mixture may then be incubated at room temperature for 60 min,and quenched and developed by addition of 10 μL of luciferase reagent.Luminescence intensities of the resulting reaction mixtures may bemeasured after a 10 min incubation at room temperature. The luminescenceintensity may be measured by using the Analyst HT from LJL Biosystems.

pK_(act) and % ACT_(max) values may be calculated by non-linear curvefitting of the compound concentrations and luminescence intensities to astandard inhibition/activation equation. K_(act) is the concentrationthat displays 50% of the maximal increase in GK activity observed usinga saturating activator concentration. % Act_(max) represents thecalculated maximal gain in GK enzyme activity at a saturatingconcentration of the compound. pK_(act) and % ACT_(max) values forselect compounds of the present invention are given in Table 1.

TABLE 1 pK_(act) and % ACT_(max) of Exemplified Compounds Against GKCompound pK_(act) % ACT_(max) 1 ≦4.8 ≦90 2 ≦4.8 ≦90 3 ≦4.8 ≦90 4 4.9-5.4101-105 5 5.9-6.4 ≧111  6 4.9-5.4 ≧111  7 4.9-5.4 ≦90 8 4.9-5.4 ≦90 94.9-5.4 ≦90 10 5.5-5.8 ≧111  11 ≧6.5 101-105 12 5.5-5.8 ≦90 13 ≧6.5106-110 14 ≧6.5 ≧111  15 5.9-6.4  90-100 16 ≧6.5 106-110 19 ≧6.5 ≦90  20(Free Base) 5.9-6.4 101-105  20 (TFA Salt) 5.5-5.8 106-110 22 ≧6.5 ≧111 23 ≧6.5 ≧111  24 ≦4.8 ≦90 25 ≦4.8 ≦90 26 ≦4.8 ≦90 27 5.5-5.8 ≦90 284.9-5.4 ≧111  29 5.9-6.4 ≧111  30 4.9-5.4 ≦90 31 ≦4.8 ≦90 32 4.9-5.4101-105 33 5.5-5.8 ≧111  34 5.5-5.8 ≧111  35 ≦4.8 ≦90 36 5.5-5.8 ≧111 37 5.5-5.8 ≧111  38 ≦4.8 ≧111  39 5.5-5.8 ≧111  40 ≦4.8 ≦90 41 5.5-5.8≦90 42 5.5-5.8 ≧111  43 ≦4.8 ≦90 44 5.9-6.4 ≧111  45 4.9-5.4 ≧111  46≦4.8 101-105 47 4.9-5.4 ≧111  48 5.9-6.4 ≧111  49 4.9-5.4  90-100 50≦4.8 ≦90 51 5.9-6.4 ≧111  52 ≦4.8  90-100 53 ≦4.8 ≦90 54 4.9-5.4 ≦90 554.9-5.4 ≦90 56 ≦4.8 ≦90 57 4.9-5.4 101-105 58 ≦4.8 101-105 59 ≧6.5106-110 60 ≦4.8 ≦90 61 5.9-6.4  90-100 62 5.9-6.4  90-100 63 4.9-5.4≧111  64 ≧6.5 ≧111  65 5.9-6.4  90-100 66 ≧6.5 101-105 67 ≧6.5 106-11068 4.9-5.4 101-105 69 ≧6.5 106-110 70 5.5-5.8 101-105 71 5.5-5.8 ≦90 72≧6.5 ≦90 73 ≦4.8  90-100 74 5.5-5.8  90-100 75 5.9-6.4  90-100 76 ≧6.5106-110 77 ≦4.8 101-105 78 5.5-5.8  90-100 79 ≧6.5  90-100 80 ≧6.5101-105 81 4.9-5.4 101-105 82 ≧6.5 106-110 83 4.9-5.4 ≦90 84 ≧6.5106-110 85 5.5-5.8  90-100 86 ≦4.8 ≦90 87 5.5-5.8  90-100 88 ≦4.8 ≦90 895.5-5.8 101-105 90 ≦4.8  90-100 91 5.9-6.4 101-105 92 4.9-5.4 ≦90 93≦4.8 ≦90 94 ≧6.5  90-100 95 5.5-5.8 101-105 96 5.9-6.4 101-105 975.9-6.4 106-110 98 5.9-6.4  90-100 99 4.9-5.4  90-100 100 5.9-6.4 ≦90101 5.9-6.4  90-100 102 5.9-6.4  90-100 103 5.5-5.8 101-105 104 5.5-5.8 90-100 105 (TFA Salt)  5.9-6.4 ≦90 105 (Free Base) ≧6.5 ≦90 106 ≦4.8 90-100 107 ≧6.5 ≧111  108 4.9-5.4 ≧111  109 ≧6.5 101-105 110 ≦4.8106-110 111 5.9-6.4 106-110 112 ≧6.5 106-110 113 5.9-6.4 101-105 114≧6.5 101-105 115 ≧6.5 106-110 116 4.9-5.4 ≦90 117 ≧6.5 106-110 118 ≦4.8≦90 119 5.9-6.4  90-100 120 ≧6.5  90-100 121 ≧6.5  90-100 122 4.9-5.4≧111  123 ≧6.5 ≧111  124 4.9-5.4 ≧111  125 5.5-5.8 ≧111  126 ≦4.8 ≦90127 ≧6.5 101-105 128 ≧6.5  90-100 129 4.9-5.4 ≦90 130 ≧6.5 101-105 131≦4.8 ≦90 132 5.5-5.8  90-100 133 ≧6.5 101-105 134 5.5-5.8 ≧111  1355.9-6.4 106-110 136 5.9-6.4 ≧111  137 4.9-5.4 ≦90 138 5.9-6.4  90-100139 ≦4.8 106-110 140 ≦4.8 ≦90 141 ≧6.5  90-100 142 ≧6.5 101-105 143 ≧6.5≦90 144 ≧6.5 106-110 145 4.9-5.4 ≦90 146 4.9-5.4 ≦90 147 5.5-5.8 ≧111 148 4.9-5.4 ≦90 149 ≧6.5 ≧111  150 5.9-6.4 ≧111  151 5.5-5.8  90-100 152≧6.5 106-110 153 ≦4.8 106-110 154 ≧6.5 106-110 155 ≧6.5 106-110 156 ≧6.5101-105 157 5.9-6.4 ≧111  158 5.9-6.4 ≧111  159 5.5-5.8 101-105 1604.9-5.4  90-100 161 ≦4.8 ≦90 162 5.5-5.8 106-110 163 5.5-5.8 ≦90 1645.9-6.4 106-110 165 ≧6.5  90-100 166 4.9-5.4  90-100 167 4.9-5.4 ≦90 168≦4.8 ≦90 169 ≦4.8 ≦90 170 ≦4.8 ≦90 171 5.5-5.8 106-110

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the compounds, compositions,kits, and methods of the present invention without departing from thespirit or scope of the invention. Thus, it is intended that the presentinvention cover the modifications and variations of this inventionprovided they come within the scope of the appended claims and theirequivalents.

1. A compound of the formula:

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein R₁ is selected from thegroup consisting of hetero(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,heteroaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted; R₂ is selected from the group consisting of hydrogen anda substituent convertible to hydrogen in vivo; R₃ is selected from thegroup consisting of hydrogen, carbonyl, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₃ is -L-R₁₈; R₄ is selected from thegroup consisting of hydrogen, carbonyl, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₃ and R₄ are taken together to form asubstituted or unsubstituted ring; R₅ is selected from the groupconsisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted; R₆ is selected from the group consistingof hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₆ is -L₁-R₂₂; R₇ is selected from the groupconsisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₇ is -L₁-R₂₂; or any two R₅, R₆ and R₇are taken together to form a substituted or unsubstituted ring; L is alinker providing 0, 1, 2, 3, 4, 5 or 6 atom separation between the C andR₁₈ to which L is attached, wherein the atoms of the linker providingthe separation are selected from the group consisting of carbon, oxygen,nitrogen, and sulfur; L₁ is absent or a linker providing 1, 2, 3, 4, 5or 6 atom separation between R₂₂ and the ring to which L₁ is attached,wherein the atoms of the linker providing the separation are selectedfrom the group consisting of carbon, oxygen, nitrogen, and sulfur; R₁₈is selected from the group consisting of hydrogen, halo, nitro, cyano,thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted; R₂₂ is selected from the group consistingof hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring, with the provisos that (a) R₁ isnot 5-(3-acetamidocyclobutyl)-1H-pyrazol-3-yl when R₅ and R₆, togetherwith the ring to which they are attached, form an unsubstitutedindazol-1-yl; and (b) R₁ is not 5-(2-chlorobenzyl)thiazol-2-yl when R₃is phenyl and R₂, R₄, R₅, R₆ and R₇ are all hydrogen. 2-5. (canceled) 6.The compound of claim 1 comprising:

wherein n′ is selected from the group consisting of 0, 1, 2 and 3; andR₈ is selected from the group consisting of hydrogen, halo, nitro,cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, (C₃₋₁₂)cycloalkylsulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈are taken together to form a substituted or unsubstituted ring.
 7. Thecompound according to claim 6, wherein R₈ is selected from the groupconsisting of hydrogen, halo, a substituted or unsubstituted(C₁₋₃)alkyl, a substituted or unsubstituted sulfonyl(C₁₋₃)alkyl, asubstituted or unsubstituted (C₁₋₃)alkylsulfonyl and a substituted orunsubstituted (C₃₋₁₂)cycloalkylsulfonyl.
 8. The compound according toclaim 6, wherein R₈ is selected from the group consisting ofsulfonylmethyl, methylsulfonyl, cyclopropylsulfonyl andcyclopentylsulfonyl, each substituted or unsubstituted.
 9. The compoundaccording to claim 6, wherein R₈ is -L₁-R₂₂; L₁ is absent or a linkerproviding 1, 2, 3, 4, 5 or 6 atom separation between R₂₂ and the ring towhich L₁ is attached, wherein the atoms of the linker providing theseparation are selected from the group consisting of carbon, oxygen,nitrogen, and sulfur; R₂₂ is selected from the group consisting ofhydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.
 10. The compound according to claim6, wherein R₈ is —SO₂—R₂₂; R₂₂ is selected from the group consisting ofhydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.
 11. The compound according to claim6, wherein R₃ is a substituted or unsubstituted(tetrahydro-2H-pyran-4-yl)methyl and R₈ is a substituted orunsubstituted cyclopropylsulfonyl.
 12. The compound of claim 1 havingthe formula:

or a pharmaceutical acceptable salt thereof, wherein n is selected fromthe group consisting of 0, 1, 2, 3 and 4; and R₈ is selected from thegroup consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy,aryloxy, heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈are taken together to form a substituted or unsubstituted ring.
 13. Thecompound according to claim 12, wherein R₈ is selected from the groupconsisting of hydrogen, halo, a substituted or unsubstituted(C₁₋₃)alkyl, a substituted or unsubstituted sulfonyl(C₁₋₃)alkyl, asubstituted or unsubstituted (C₁₋₃)alkylsulfonyl and a substituted orunsubstituted (C₃₋₁₂)cycloalkylsulfonyl.
 14. The compound according toclaim 12, wherein R₈ is selected from the group consisting ofsulfonylmethyl, methylsulfonyl, cyclopropylsulfonyl andcyclopentylsulfonyl, each substituted or unsubstituted.
 15. The compoundaccording to claim 12, wherein R₈ is -L₁-R₂₂; L₁ is absent or a linkerproviding 1, 2, 3, 4, 5 or 6 atom separation between R₂₂ and the ring towhich L₁ is attached, wherein the atoms of the linker providing theseparation are selected from the group consisting of carbon, oxygen,nitrogen, and sulfur; R₂₂ is selected from the group consisting ofhydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.
 16. The compound according to claim12, wherein R₈ is —SO₂—R₂₂; R₂₂ is selected from the group consisting ofhydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.
 17. The compound according to claim12, wherein R₃ is a substituted or unsubstituted(tetrahydro-2H-pyran-4-yl)methyl and R₈ is a substituted orunsubstituted cyclopropylsulfonyl.
 18. The compound of claim 1 havingthe formula:

or a pharmaceutically acceptable salt thereof wherein n′ is selectedfrom the group consisting of 0, 1, 2 and 3; and R₈ is selected from thegroup consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy,aryloxy, heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, (C₃₋₁₂)cycloalkyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₈ is -L₁-R₂₂, or R₈ and R₇ or two R₈are taken together to form a substituted or unsubstituted ring.
 19. Thecompound according to claim 18, wherein R₈ is selected from the groupconsisting of hydrogen, halo, a substituted or unsubstituted(C₁₋₃)alkyl, a substituted or unsubstituted sulfonyl(C₁₋₃)alkyl, asubstituted or unsubstituted (C₁₋₃)alkylsulfonyl and a substituted orunsubstituted (C₃₋₁₂)cycloalkylsulfonyl.
 20. The compound according toclaim 18, wherein R₈ is selected from the group consisting ofsulfonylmethyl, methylsulfonyl, cyclopropylsulfonyl andcyclopentylsulfonyl, each substituted or unsubstituted.
 21. The compoundaccording to claim 18, wherein R₈ is -L₁-R₂₂; L₁ is absent or a linkerproviding 1, 2, 3, 4, 5 or 6 atom separation between R₂₂ and the ring towhich L₁ is attached, wherein the atoms of the linker providing theseparation are selected from the group consisting of carbon, oxygen,nitrogen, and sulfur; R₂₂ is selected from the group consisting ofhydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.
 22. The compound according to claim18, wherein R₈ is —SO₂—R₂₂; R₂₂ is selected from the group consisting ofhydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.
 23. The compound according to claim18, wherein R₃ is a substituted or unsubstituted(tetrahydro-2H-pyran-4-yl)methyl and R₈ is a substituted orunsubstituted cyclopropylsulfonyl. 24-71. (canceled)
 72. The compoundaccording to claim 1, wherein R₁ is a substituted or unsubstitutedheteroaryl.
 73. The compound according to claim 1, wherein R₁ isselected from the group consisting of thiazolyl, pyrazinyl, pyrazolyland pyridyl, each substituted or unsubstituted.
 74. The compoundaccording to claim 1, wherein R₁ is selected from the group consistingof thiazol-2-yl; 2-pyridyl; 5-methyl-thiazol-2-yl; 6-methyl-pyrid-2-yl;4-methyl-pyrid-2-yl; 5-bromo-6-methyl-pyrid-2-yl; 5-phenyl-pyrid-2-yl;benzothiazol-2-yl; a nicotinic acid methyl ester; 5-bromo-pyrid-2-yl;2-pyrazinyl; 1-methyl-pyrazol-3-yl and 5-fluoro-thiazol-2-yl. 75.(canceled)
 76. The compound according to claim 1, wherein R₁ is selectedfrom the group consisting of:

wherein R₁₄ is selected from the group consisting of hydrogen, halo,nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxamido, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, oxa(C₁₋₅)alkyl, oxo(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₁₄ is -L₁-R₂₂. 77-79. (canceled) 80.The compound according to claim 1, wherein R₂ is hydrogen.
 81. Thecompound according to claim 1, wherein R₃ is -L-R₁₈; L is a linkerproviding 0, 1, 2, 3, 4, 5 or 6 atom separation between the C and R₁₈ towhich L is attached, wherein the atoms of the linker providing theseparation are selected from the group consisting of carbon, oxygen,nitrogen, and sulfur; and R₁₈ is selected from the group consisting ofhydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted.
 82. The compound according to claim 1, wherein R₃ has theformula:

wherein p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7, 8 and 9; L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atomseparation between the C and the ring to which L is attached, whereinthe atoms of the linker providing the separation are selected from thegroup consisting of carbon, oxygen, nitrogen, and sulfur; Q is selectedfrom the group consisting of O, S, CS, CO, SO, SO₂, CR₁₉R₂₀ and NR₂₁;R₁₃ is selected from the group consisting of hydrogen, halo, nitro,cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or two R₁₃ are taken together to form asubstituted or unsubstituted ring; R₁₉ and R₂₀ are each independentlyselected from the group consisting of hydrogen, halo, nitro, cyano,thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted; and R₂₁ is selected from the groupconsisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted.
 83. The compound according to claim 1,wherein L is selected from the group consisting of —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —C(O)—, —CH₂C(O)—, —C(O)CH₂—, —CH₂—C(O)CH₂—, —C(O)CH₂CH₂—,—CH₂CH₂C(O)—, —O—, —OCH₂—, —CH₂O—, —CH₂OCH₂—, —OCH₂CH₂—, —CH₂CH₂O—,—N(CH₃)—, —NHCH₂—, —CH₂NH—, —CH₂NHCH₂—, —NHCH₂CH₂—, —CH₂CH₂NH—,—NH—C(O)—, —NCH₃—C(O)—, —C(O)NH—, —C(O)NCH₃—, —NHC(O)CH₂—, —C(O)NHCH₂—,—C(O)CH₂NH—, —CH₂NHC(O)—, —CH₂C(O)NH—, —NHCH₂C(O)—, —S—, —SCH₂—, —CH₂S—,—SCH₂CH₂—, —CH₂SCH₂—, —CH₂CH₂S—, —C(O)S—, —C(O)SCH₂—, —CH₂C(O)S—,—C(O)CH₂S—, and —CH₂SC(O)—, each substituted or unsubstituted.
 84. Thecompound according to claim 1, wherein L is selected from the groupconsisting of —(CR₂₄R₂₅)_(s)—; s is selected from the group consistingfrom the group consisting of 1, 2, 3, 4, 5 and 6; and R₂₄ and R₂₅ areeach independently selected from the group consisting of hydrogen, halo,nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido,amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted.
 85. The compound according to claim 1, wherein L is—CH₂—.
 86. The compound according to claim 1, wherein R₄ is hydrogen.87. The compound according to claim 1, wherein R₅ is selected from thegroup consisting of hydrogen, halo and a substituted or unsubstituted(C₁₋₃)alkyl.
 88. The compound according to claim 1, wherein R₆ isselected from the group consisting of hydrogen, halo, a substituted orunsubstituted (C₁₋₃)alkyl; a substituted or unsubstituted(C₁₋₃)alkylsulfonyl and a substituted or unsubstituted(C₃₋₆)cycloalkylsulfonyl.
 89. The compound according to claim 1, whereinR₆ is -L₁-R₂₂; L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6atom separation between R₂₂ and the ring to which L₁ is attached,wherein the atoms of the linker providing the separation are selectedfrom the group consisting of carbon, oxygen, nitrogen, and sulfur; R₂₂is selected from the group consisting of hydrogen, halo, nitro, cyano,thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ areeach independently selected from the group consisting of hydrogen,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.
 90. The compound according to claim1, wherein R₇ is selected from the group consisting of hydrogen, haloand a substituted or unsubstituted (C₁₋₃)alkyl.
 91. The compoundaccording to claim 1, wherein R₇ is -L₁-R₂₂; L₁ is absent or a linkerproviding 1, 2, 3, 4, 5 or 6 atom separation between R₂₂ and the ring towhich L₁ is attached, wherein the atoms of the linker providing theseparation are selected from the group consisting of carbon, oxygen,nitrogen, and sulfur; R₂₂ is selected from the group consisting ofhydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₂₂ is —NR₂₇R₂₈; and R₂₇ and R₂₈ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.
 92. The compound according to claim1, wherein R₅ and R₆, together with the atoms to which they areattached, form a substituted or unsubstituted aryl.
 93. The compoundaccording to claim 1, wherein R₅ and R₆, together with the atoms towhich they are attached, form a substituted or unsubstituted heteroaryl.94. The compound according to claim 1, wherein R₂₂ is selected from thegroup consisting of a substituted or unsubstituted (C₁₋₅)alkyl; asubstituted or unsubstituted (C₃₋₆)cycloalkyl; a substituted orunsubstituted (C₄₋₈)aryl; and a substituted or unsubstitutedhetero(C₁₋₆)aryl.
 95. The compound according to claim 1, wherein R₂₂ iscyclopropyl.
 96. The compound according to claim 1, wherein R₂₂ is—NR₂₇R₂₈; and R₂₇ and R₂₈ are each independently selected from the groupconsisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,aryl, heteroaryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted, or R₂₇ and R₂₈ are taken together to forma substituted or unsubstituted ring.
 97. The compound according to claim1, wherein L₁ is selected from the group consisting of —(CR₂₄R₂₅)_(s)—,—NR₂₆—, —O—, —S—, —CO—, —CS—, —SO—, —SO₂—, and combinations thereof; sis selected from the group consisting from the group consisting of 1, 2,3, 4, 5 and 6; R₂₄ and R₂₅ are each independently selected from thegroup consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted; and R₂₆ is selected from the groupconsisting of hydrogen, cyano, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido,amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted.
 98. The compound according to claim 1, wherein L₁ is—SO₂—.
 99. The compound according to claim 1, wherein the compound is inthe form of a pharmaceutically acceptable salt.
 100. A pharmaceuticalcomposition comprising as an active ingredient a compound according toclaim 1, and one or more pharmaceutically acceptable excipients.101-108. (canceled)
 109. A method of treating a disease state in asubject, the method comprising administering a compound orpharmaceutically acceptable salt as defined in claim 1 to the subject,wherein the compound is selected from the group consisting ofhyperglycemia, diabetes, dyslipidaemia, obesity, insulin resistance,metabolic syndrome X, impaired glucose tolerance, polycystic ovarysyndrome, and cardiovascular disease.
 110. (canceled)